\r\n\tThe study of populations and plant communities in their different aspects; ecological, structural, functional and dynamic, it is essential to establish a posteriori models of forest and agricultural management.
\r\n\r\n\tFor this, the methodological approaches on the type of sampling are considered essential, since there are differences between the purely ecological and the phytosociological methods, despite the fact that both pursue the same objective.
\r\n\tAlthough the ecological method for the knowledge of the vegetation is widely extended, the phytosociological one is no less so, since in the European Union it has been developed as a consequence of policies on sustainability, through which regulations have been issued, such as the habitats directive.
\r\n\tOn the other hand, research on plant dynamics and knowledge of the landscape in an integral way, have multiplied in the last 30 years, which has favored a deep knowledge of the floristic and phytocenotic wealth, which is fundamental for agricultural management, livestock and forestry.
",isbn:"978-1-83969-386-1",printIsbn:"978-1-83969-385-4",pdfIsbn:"978-1-83969-387-8",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"0abf2a59ee63fc1ba4fb64d77c9b1be7",bookSignature:"Dr. Eusebio Cano Carmona, Dr. Ricardo Quinto Canas, Dr. Ana Cano Ortiz and Dr. Carmelo Maria Musarella",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/9662.jpg",keywords:"Climatic Factors, Bioclimate, Thermotype, Flora, Conservation, Phytocenosis, Plant Dynamics, Landscape, Cartography, Vegetation Series, Crops, Reforestation",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 23rd 2020",dateEndSecondStepPublish:"January 25th 2021",dateEndThirdStepPublish:"March 26th 2021",dateEndFourthStepPublish:"June 14th 2021",dateEndFifthStepPublish:"August 13th 2021",remainingDaysToSecondStep:"2 days",secondStepPassed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"Dr. Cano Carmona and colleagues have directed 12 doctoral theses and more than 200 publications among articles, books, and book chapters. He has participated in national and international congresses with about 250 papers. He has held a number of different academic positions, including Dean of the Faculty of Experimental Sciences at the University of Jaen, Spain, and founder and director of the International Seminar on Management and Conservation of Biodiversity.",coeditorOneBiosketch:"Ricardo Jorge Quinto Canas is currently an Invited Assistant Professor in the Faculty of Sciences and Technology at the University of Algarve – Portugal, and a member of the Centre of Marine Sciences (CCMAR), University of Algarve. His current research projects focus on Botany, Vegetation Science (Geobotany), Biogeography, Plant Ecology, and Biology Conservation, aiming to support Nature Conservation.",coeditorTwoBiosketch:"Ana Cano Ortiz's fundamental line of research is related to botanical bioindicators. She has worked in Spain, Italy, Portugal, and Central America. It presents more than one hundred works published in various national and international journals, as well as books and book chapters; and has presented a hundred papers to national and international congresses.",coeditorThreeBiosketch:"Carmelo Maria Musarella is a biologist, specialized in Plant Biology. He is a member of the permanent scientific committee of the International Seminar on “Biodiversity Conservation and Management” guested by several European universities. He has participated in several international and national congresses, seminars, and workshops and presented oral communications and posters.",coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"87846",title:"Dr.",name:"Eusebio",middleName:null,surname:"Cano Carmona",slug:"eusebio-cano-carmona",fullName:"Eusebio Cano Carmona",profilePictureURL:"https://mts.intechopen.com/storage/users/87846/images/system/87846.png",biography:"Eusebio Cano Carmona obtained a PhD in Sciences from the\nUniversity of Granada, Spain. He is Professor of Botany at the\nUniversity of Jaén, Spain. His focus is flora and vegetation and he\nhas conducted research in Spain, Italy, Portugal, Palestine, the\nCaribbean islands and Mexico. As a result of these investigations,\nDr. Cano Carmona and colleagues have directed 12 doctoral theses\nand more than 200 publications among articles, books and book\nchapters. He has participated in national and international congresses with about\n250 papers/communications. He has held a number of different academic positions,\nincluding Dean of the Faculty of Experimental Sciences at the University of Jaen,\nSpain and founder and director of the International Seminar on Management and\nConservation of Biodiversity, a position he has held for 13 years. He is also a member of the Spanish, Portuguese and Italian societies of Geobotany.",institutionString:"University of Jaén",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"5",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"University of Jaén",institutionURL:null,country:{name:"Spain"}}}],coeditorOne:{id:"216982",title:"Dr.",name:"Ricardo Quinto",middleName:null,surname:"Canas",slug:"ricardo-quinto-canas",fullName:"Ricardo Quinto Canas",profilePictureURL:"https://mts.intechopen.com/storage/users/216982/images/system/216982.JPG",biography:"Ricardo Quinto Canas, Phd in Analysis and Management of Ecosystems, is currently an Invited Assistant Professor in the Faculty\nof Sciences and Technology at the University of Algarve, Portugal, and member of the Centre of Marine Sciences (CCMAR),\nUniversity of Algarve. He is also the Head of Division of Environmental Impact Assessment - Algarve Regional Coordination\nand Development Commission (CCDR - Algarve). His current\nresearch projects focus on Botany, Vegetation Science (Geobotany), Biogeography,\nPlant Ecology and Biology Conservation, aiming to support Nature Conservation.\nDr. Quinto Canas has co-authored many cited journal publication, conference articles and book chapters in above-mentioned topics.",institutionString:"University of Algarve",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"0",institution:null},coeditorTwo:{id:"203697",title:"Dr.",name:"Ana",middleName:null,surname:"Cano Ortiz",slug:"ana-cano-ortiz",fullName:"Ana Cano Ortiz",profilePictureURL:"https://mts.intechopen.com/storage/users/203697/images/system/203697.png",biography:"Ana Cano Ortiz holds a PhD in Botany from the University of\nJaén, Spain. She has worked in private enterprise, in university\nand in secondary education. She is co-director of four doctoral\ntheses. Her research focus is related to botanical bioindicators.\nDr. Ortiz has worked in Spain, Italy, Portugal and Central America. She has published more than 100 works in various national\nand international journals, as well as books and book chapters.\nShe has also presented a great number of papers/communications to national and\ninternational congresses.",institutionString:"University of Jaén",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"6",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Jaén",institutionURL:null,country:{name:"Spain"}}},coeditorThree:{id:"276295",title:"Dr.",name:"Carmelo Maria",middleName:null,surname:"Musarella",slug:"carmelo-maria-musarella",fullName:"Carmelo Maria Musarella",profilePictureURL:"https://mts.intechopen.com/storage/users/276295/images/system/276295.jpg",biography:"Carmelo Maria Musarella, PhD (Reggio Calabria, Italy –\n23/01/1975) is a biologist, specializing in plant biology. He\nstudied and worked in several European Universities: Messina,\nCatania, Reggio Calabria, Rome (Italy), Valencia, Jaén, Almeria\n(Spain), and Evora (Portugal). He was the Adjunct Professor\nof Plant Biology at the “Mediterranea” University of Reggio\nCalabria (Italy). His research topics are: floristic, vegetation,\nhabitat, biogeography, taxonomy, ethnobotany, endemisms, alien species, and\nbiodiversity conservation. He has authored many research articles published in\nindexed journals and books. He has been the guest editor for Plant Biosystems and a\nreferee for this same journal and others. He is a member of the permanent scientific\ncommittee of International Seminar on “Biodiversity Conservation and Management”, which includes several European universities. He has participated in several\ninternational and national congresses, seminars, workshops, and presentations of\noral communications and posters.",institutionString:'"Mediterranea" University of Reggio Calabria',position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"6",totalChapterViews:"0",totalEditedBooks:"1",institution:null},coeditorFour:null,coeditorFive:null,topics:[{id:"5",title:"Agricultural and Biological Sciences",slug:"agricultural-and-biological-sciences"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"247865",firstName:"Jasna",lastName:"Bozic",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/247865/images/7225_n.jpg",email:"jasna.b@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"6893",title:"Endemic Species",subtitle:null,isOpenForSubmission:!1,hash:"3290be83fff5bc015f5bd3d78ae9c6c7",slug:"endemic-species",bookSignature:"Eusebio Cano Carmona, Carmelo Maria Musarella and Ana Cano Ortiz",coverURL:"https://cdn.intechopen.com/books/images_new/6893.jpg",editedByType:"Edited by",editors:[{id:"87846",title:"Dr.",name:"Eusebio",surname:"Cano Carmona",slug:"eusebio-cano-carmona",fullName:"Eusebio Cano Carmona"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6418",title:"Hyperspectral Imaging in Agriculture, Food and Environment",subtitle:null,isOpenForSubmission:!1,hash:"9005c36534a5dc065577a011aea13d4d",slug:"hyperspectral-imaging-in-agriculture-food-and-environment",bookSignature:"Alejandro Isabel Luna Maldonado, Humberto Rodríguez Fuentes and Juan Antonio Vidales Contreras",coverURL:"https://cdn.intechopen.com/books/images_new/6418.jpg",editedByType:"Edited by",editors:[{id:"105774",title:"Prof.",name:"Alejandro Isabel",surname:"Luna Maldonado",slug:"alejandro-isabel-luna-maldonado",fullName:"Alejandro Isabel Luna Maldonado"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"54855",title:"Novel Antimicrobial Agents and Processes for Textile Applications",doi:"10.5772/intechopen.68423",slug:"novel-antimicrobial-agents-and-processes-for-textile-applications",body:'\nFibres, both natural and man-made, have been widely used since the ancient past in the manufacture of other materials. World fibre consumption has strongly increased over the years, reaching a total demand of 94.9 million tons in 2015. In detail, 66.8 million tons were man-made fibres, in addition to natural fibres with a demand of 28.1 million tons [1].
\nNowadays, besides the traditional clothing products, textiles find important applications also in home furnishing, food packaging, as fibre reinforcements for polymers, optical fibres, thermal and mechanical protection, sport equipment, fibrous materials for a large array of applications in medicine and hygiene such as medical devices, health care and hygienic coatings, air filters and water purification systems.
\nAn important example of these functional fabrics, recently attracting the interest of the research, is antimicrobial fabrics. Due to the morphology of fibres, in particular those of natural origin, textiles are prone to microorganisms’ growth on their surface, due to the large surface area and moisture affinity. Bacteria and fungi can be found everywhere, so the contact with textiles is extremely probable. Depending on moisture, nutrients, temperature and pH, their growth can be very fast: some bacteria can double every 20 min [2].
\nThe undesirable effects caused by microorganisms’ growth act both on the textile itself and on the user. Unpleasant odour, reduction of mechanical strength, stains and discolouration are all effects of the biodeterioration of textiles, affecting almost all the types of fibres. Natural fibres are generally more susceptible to biodeterioration than the man-made fibres, because their porous hydrophilic structure retains water, oxygen and nutrients, providing perfect environments for bacterial growth. Finishing agents can also promote microbial growth [3]. Even mild surface growth can make a fabric unattractive by the appearance of unwanted pigmentation; heavy infestation which results in rotting and breakdown of the fibres may cause the fabric deterioration, in fact microorganisms can accelerate the hydrolysis of cellulose. Man-made fibres derived from cellulose are susceptible to microbial deterioration. Viscose is readily attacked by mildews and bacteria while acetate and triacetate are more resistant, but discolouration can occur if the fabrics are incorrectly stored. Synthetic fibres show strong resistance to attack by microorganisms, due to the hydrophobic nature of the polymers, but the presence of contaminants can cause some bacterial attack [3].
\nMost of the microorganisms involved in textile contaminations can cause pathogenic effects. Many species, such as Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa, Staphylococcus aureus and Acinetobacter baumannii, can cause infections to human beings due to user contaminations. It is a great concern for textiles used mainly in hospitals, as medical devices or for health and hygienic care, and in crowded places, but also in sport and underwear clothing, water purification systems, animal feed and food industry. Therefore, the demand for antimicrobial textiles is gaining interest, showing a strong increase over the last few years: the global market for antimicrobial agents is expected to increase by about 12% each year between 2013 and 2018 [4].
\nDifferent methods were investigated to confer antimicrobial activity to textiles; they can be classified into the inclusion of antimicrobial leaching compounds in the polymeric fibres, the surface modification of the fibres by grafting reactions or by physical methods.
\nBesides the efficiency towards a broad spectrum of microorganisms, any antimicrobial treatment should consider other challenges. First, it has to be non-toxic to the end user of the textile, namely cytotoxicity, allergy, irritation or sensitization must be avoided. The treatment must have a good fastness to use, mainly to repeated laundering, dry cleaning and ironing, and should not compromise the quality, hand or appearance of the textile. The application method should be simple, easily implementable in the finishing process and environmentally friendly, avoiding side effects for the manufacturers. Finally, the antimicrobial agent should not kill the resident flora of non-pathogenic bacteria on the skin of the wearer. Thus, the study on new and efficient antimicrobial treatments for textiles, considering both the antimicrobial agent and the application method, is a relevant topic of the research.
\nThe aim of this chapter is to provide an overview of recently developed antimicrobial treatments to produce antimicrobial textiles. Afterwards, the discussion will be focused and detailed on chitosan and polypyrrole (PPy), two promising antimicrobial agents deeply investigated by the authors for textile applications.
\nDepending on the fibre type, that is morphology, composition and surface texture, and on the applied antimicrobial agent, different chemical or physical approaches are possible and under development to confer antimicrobial activity to textiles.
\nIn the case of synthetic fibres, a specific antimicrobial agent can be directly incorporated into the polymeric matrix [5].
\nThe application of the antimicrobial agent on the fibre’s surface, during the finishing stage, is a viable method both for synthetic and natural fibres; it can be carried out by the traditional pad-dry-cure technique or exhaustion bath.
\nThe recent growing interest on nanotechnology concerns also the textile field; in fact nanoscale particles can be prepared from natural or synthetic compounds with antibacterial activity and applied to textiles, for example, by foulard. The advantage is the lower add-on enough to confer the desired property due to the high surface area of the nanoparticles. Moreover, coupling the process with a final cross-linking, a good fastness of the finishing can be obtained [6]. Electrospinning to produce intrinsically antimicrobial nanofibres is another interesting application of nanotechnology; in this case, the nanofibres can be coupled with other natural or synthetic fibres to produce antimicrobial yarns [7].
\nMicroencapsulation is a process by which droplets of liquid or particles of solid are covered with a continuous film of polymeric material [8]. This technology is one of the most promising techniques to confer functional properties to textiles: the capsules are applied to fibres as dispersion with a binder using padding, spraying, impregnation, exhaust or screen-printing techniques. It is more advantageous than the conventional processes in terms of economy, energy saving, eco-friendliness and controlled release of substances, but it can affect the handle of the textile [9].
\nAn effective way to embed the antimicrobial agent in the fibre is cross-linking. Cross-linking happens when a cross-linker makes intermolecular covalent bridges between the polymer chains and the antibacterial molecule. Cross-linkers include glutaraldehyde, genipin, glyoxal, dextran sulphate, 1,1,3,3-tetramethoxypropane, oxidized cyclodextrins, ethylene glycol diglyceryl ether, ethylene glycol diglycidyl ether (EGDE) and diisocyanate [10, 11].
\nCross-linking can occur by chemical [12], radiation [13] or physical method [14]. In radiation, cross-linking, heat or a catalyst are not needed, thus no additional toxic chemical is introduced into the system and the substrate is preserved by a thermal degradation. The physical method is based on ionic interactions between polymer chains, so it is not as durable as the chemical or radiation ones.
\nFinally, altering the surface properties of fibres is also an interesting way to ensure a strong adhesion of finishing agents to textiles. Surface modification methods, such as oxygen plasma treatment, ultrasound technology, UV radiation, surface bridging and enzyme treatment, have been recently investigated, with the aim to impart durable antimicrobial finishes to fabrics using mainly natural products [15].
\nDepending on the application method, the antimicrobial textile can act by contact or by diffusion. In the first case, the antimicrobial agent is placed on the surface of the substrate and no leaching occurs; it will act only in case of direct contact between the microorganism and the fibres. In the second case, the agent will migrate from the textile to the external environment, to attack the microorganisms. It means that the antimicrobial activity of the textile can decrease with time, and that the impact of the antimicrobial agent on the environment has to be considered.
\nAccording to its action against the microorganisms’ cell, an antimicrobial agent can be classified as biostatic or biocidal. The first ones can just inhibit the cell growth, whereas biocidal agents can kill the microorganisms. Most of the antimicrobial agents used in commercial textile finishing are biocides, acting by damage or inhibition of cell wall synthesis, inhibition of cell membrane function, of protein synthesis, of DNA and RNA synthesis or of other metabolic processes.
\nQuaternary ammonium compounds (QACs) are cationic agents carrying a positive charge at the N atom in solution (R4N+X⁻); they are usually attached to an anionic fibre surface (polyester, cotton, nylon and wool) by ionic interaction. The molecule is a linear alkyl ammonium chain composed of a hydrophobic alkyl chain (C12–C18) and a hydrophilic counterpart.
\nThe antimicrobial action, depending on alkyl chain length, presence of perfluorinated groups and cationic ammonium group, is due to the interaction of positive charges on the surface and cell membrane negative charges, with the consequent loss of membrane permeability and cell leakage. It causes the damage of cell membranes, the denaturation of proteins and the inhibition of DNA production [16].
\nQACs are effective against Gram-positive and Gram-negative bacteria, fungi and certain types of viruses; for this reason, these are widely used in industrial applications [17]. The disadvantage is the poor fastness of the treatment due to the fast leaching from the textile for the lack of chemical or physical bonding [18].
\nCommercial products based on QAC are BIOGUARD® (AEGIS Microbe Shield, New Zealand), Sanigard KC® (LN Chemical Industries, Switzerland) and Sanitized® (SANITIZED, Switzerland) [19].
\nTriclosan is a 2,4,4’-trichloro-2’hydroxydiphenyl ether (C12H7Cl3O2), a synthetic chlorinated bisphenol not ionized in solutions, improving its durability to laundering. It can act against Gram-negative and Gram-positive bacteria and against some fungi and viruses [5, 20] by blocking lipid biosynthesis affecting the integrity of cell membranes [21].
\nTriclosan has become, in last decades, the most efficient and widely used bisphenol in many application fields. On textiles, it is mainly used in association with polyester, nylon, polypropylene, cellulose acetate and acrylic fibres [22].
\nThis recent widespread use of Triclosan had the drawback to generate bacterial resistance. Moreover, the reported photochemical conversion of Triclosan to 2,8-dichlorodibenzo-p-dioxin in aqueous solutions is another great concern, due to its toxicity [23].
\nCommercial products based on Triclosan, either as an isolated agent for a finishing or incorporated in fibres, are Microban® (Cannock, United Kingdom), Irgaguard® 1000 (Ludwigshafen, Germany), BiofresH™ (Salem, MA, USA) and Silfresh® (Magenta, Italy).
\nMetals, oxide or salt compounds, based on silver, copper, zinc or cobalt, have a strong biocidal effect due to the metal reduction potential, metal donor atom selectivity and speciation. These compounds can bind to O, N or S donor ligands present in the microorganism cell, inducing an oxidative stress, damaging cellular proteins, lipids and DNA.
\nAmong all, silver particles were widely exploited due to the broad spectrum of action against bacteria like P. aeruginosa, S. aureus, S. epidermidis, E. coli and K. pneumoniae. In textile fields, they are mainly applied in the form of salts (79%) rather than metallic (13%) or ionic (8%) form [24]. Recently, the application in the form of nanoparticles, obtained by sol-gel, is gaining interest for silver, CuO, ZnO and TiO2 [25]. It is due to the higher surface area with respect to larger particles, higher solubility and faster release of the metal ions, turning in a stronger antimicrobial effect. On ZnO, it was found that the antibacterial activity is inversely proportional to the nanoparticle size [26].
\nThe scale-up of the process to commercial scale, unfortunately, was contained due to cost, environmental and technical challenges. A plasma, UV or acidic pre-treatment is often required on fabrics to improve the treatment durability, otherwise not so good [27].
\nAvailable commercial products are mainly based on silver, in isolated form, for fibre finishing or incorporation, or already in fibre or fabric form. Some examples are Ultra-Fresh® and Silpure®, SmartSilver®, MicroFresh® and SoleFresh®, Bioactive® and Silvadur™.
\nPolyhexamethylene biguanide (PHMB) ((C8H17N5)n) is a polycationic amine in which the cationic biguanide groups are interdispersed between hydrophobic hexamethylene groups. Electrostatic and hydrophobic interactions occur with microbial cell membranes, resulting in cell membrane disruption and lethal leakage of cytoplasmic materials. Its antibacterial activity increases with the level of polymerization [28]. Some PHMB-based textile products, such as Biozac ZS and Reputex®, have already appeared on the market as finishing products [29].
\nN-halamines are heterocyclic organic compounds, with one or two covalent bonds between nitrogen and a halogen, usually chlorine (N–Cl). N-halamines can be imide, amide or amine depending on the covalent bonds formed; the antimicrobial activity increases in the same order, while the stability decreases. N-halamines present a biocide action against a broad spectrum of bacteria, fungi and viruses, binding to the acceptor regions on microorganisms, precluding the cell enzymatic and metabolic processes and causing the consequent microorganism destruction [30]. Besides the low cost and wide range action, an advantage is the possibility to recharge their antimicrobial effect of the inactive substance by simply reacting them with Cl donor compounds [31]. As a disadvantage, textiles’ treatment with N-halamine may result in a substantial amount of adsorbed Cl on the fibre surface. Those residues may produce an unpleasant odour or even discolour fabrics, which is a concerning disadvantage to the textile industry.
\nConjugated polymers, such as polypyrrole, are generally applied in textile field as electrically conductive coating in order to produce electrically conductive textiles [32, 33]. PPy can be easily produced by chemical oxidative polymerization from water solutions of the monomer. Textile materials (e.g. fibres, yarns and fabrics) soaked in the polymerization bath are coated with an even and uniform layer of PPy by in situ chemical oxidative polymerization. During the oxidative polymerization, positive charges are introduced along the backbone chain of PPy. The charges are counter-balanced by counter-ions (also called dopants or doping agents), namely anions present in the polymerization bath. The anions in the polymerization bath are embedded in the polymer matrix improving the formation and stability of positive charges along the backbone chain of PPy, delocalized over several monomer units. PPy has been a subject of several works that evaluate its properties as biocidal agent. Excellent antimicrobial properties have been shown against both Gram-negative and Gram-positive bacteria. Such a bioactivity of PPy is likely due to the presence of positive charges, even if no leaching of biocidal substances has been proven on PPy-coated fabrics. The ‘non-leaching’ approach would avoid or limit the release of toxic biocide agents to the environment or to the skin of the wearers, in the case of garments.
\nPPy nanoparticles were synthesized by chemical polymerization using ammonium persulphate as oxidant following different methods in order to evaluate the influence on the morphology of resulting nanoparticles and bactericidal activity [34]. Five systems were synthesized: conventional PPy (without surfactants), highly soluble PPy (in SDS solution), PPy/Ag colloid (in PVA solution), branched PPy and branched PPy/Ag nanocomposite (in CTAB/SDBA solution). Resulting polymer particles were investigated as active bactericidal materials against E. coli, S. aureus and K. pneumoniae. Inhibition zones, minimum inhibitory concentration (MIC) and time-kill assays were evaluated. The results indicate that the incorporation of silver nanoparticles improves the biocidal action of PPy and confirm that the size of PPy nanoparticles represents a relevant parameter for the bactericidal activity. In particular, it is possible to list the biocidal activity as follows: highly soluble PPy > branched PPy with silver > branched PPy > colloidal PPy > conventional PPy.
\nAntimicrobial activity of PPy on fabrics was first reported by Seshadri and Bhat [35] in 2005. In particular, they deposited PPy on cotton fabrics by in situ chemical oxidative polymerization at cold temperature (0–5°C). The fabrics were impregnated with monomer solutions and then the oxidant solution (ferric chloride) was added producing PPy-coated fabrics. CuCl2 was used to treat samples of PPy-coated fabrics as an additional antimicrobial agent. The biocidal properties were tested by AATCC Test Method 147-1993 and ASTM E 2149-01 using S. aureus, E. coli and Candida albicans. The microbial reductions were 65, 59 and 73%, respectively. The addition of CuCl2 to PPy increased the biocidal efficiency to 93, 98 and 100%, respectively.
\nIn another paper [36], cotton fabrics were coated with PPy at room temperature using different oxidizing agents in order to assess their antimicrobial efficacy. The fabrics were soaked in a water solution of the oxidant. The monomer was added drop-wise to the stirred bath, and the reaction lasted for 4 h producing an even black layer of PPy on the fibres of the fabrics (Figure 1).
\n(a) Picture of the PPy-coated cotton fabric and (b) SEM image of cotton fibres coated by PPy.
To obtain information about the influence of the oxidation agents on the biocidal activity, the synthesis of PPy was carried out using three different oxidants: ferric chloride, ferric sulphate and ammonium persulphate.
\nWith ferric chloride and ferric sulphate, PPy is produced by the redox reaction between the monomer and ferric ions, reduced to ferrous ions. Using ammonium persulphate, the oxidative component is persulphate ion reduced to SO4=. Using ferric sulphate and ammonium persulphate, PPy embeds SO4= ions as counter-ions, whereas the PPy produced with ferric chloride embeds Cl-. Both ferric chloride and ferric sulphate give a high acidic pH to the polymerization bath due to the production of ferric complexes with OH−. On the contrary, solutions of ammonium persulphate have a relatively low pH, due to the hydrolysis equilibrium of ammonium ions and water.
\nAntibacterial activity of PPy-coated fabrics was evaluated following the ISO 20645:2004 procedure using E. coli by placing the fabrics in contact with bacteria. No inhibition zone was observed after 24 h and the colonies grew around the fabric. The absence of colonies was observed under the fabrics in the contact zone. Therefore, there is an antibacterial activity on the fabric surface just by contact because PPy cannot diffuse being linked to the fabric. The absence of bacterial growth, even without inhibition zone, may be considered as a good antibacterial compound. Finally, the results pointed out that the antibacterial property is independent on either the oxidant used in the synthesis of PPy or the dopant embedded in the polymer matrix.
\nCotton fabrics have also been coated with PPy using dicyclohexyl sulphosuccinate (DSS) [37]. DSS has two functions: (a) it is embedded into PPy as counter-ion, similarly to several other dopants with an -SO3− group, (b) it greatly enhances the deposition process of PPy on the fabric by lowering the surface tension as a surfactant, and in turn it increases the evenness and weight uptake of PPy. In fact, the weight uptake of PPy has been 12% without DSS and 18% with DSS. The difference has been attributed primarily to the more efficient deposition due to the increased wetting of fibre surface caused by the surfactant action of DSS.
\nAntibacterial activity of the PPy-coated fabrics has been evaluated following the ASTM E 2149-01 procedure. Both the fabrics coated with PPy without DSS and PPy with DSS show 100% bacterial reduction, while untreated cotton fabric had practically no antibacterial activity. The stability of the biocidal action has been evaluated after different kinds of laundering. In particular, after dry-cleaning, fabrics coated with PPy without DSS and PPy with DSS show high bacterial reductions, 99 and 98%, respectively, whilst antibacterial efficiency decreases after launderings with non-ionic and anionic surfactants. In particular, the antibacterial activity of fabrics coated with PPy without DSS has been severely degraded by anionic laundering.
\nMoreover, the paper evaluated the biocidal mechanism of PPy by carrying out scanning electron microscopy (SEM) analysis of E. coli bacteria on cotton fibres and PPy-treated fibres. Bacteria on untreated cotton fibres had typical and regular bacterial shapes indicating that cells survived on the fibre surface. On the contrary, E. coli cells on PPy-coated fibres showed altered shapes probably due to the opening of their membrane and leakage of intracellular components from bacterial cells.
\nRecently, PPy has also been used for antimicrobial applications in combination with silver [38, 39]. In particular, Omastová et al. [40] prepared polypyrrole/silver composites by a single-step chemical oxidative polymerization using silver nitrate as an oxidant in water at room temperature. The reaction needed several days in order to yield more than 70%. The silver content in the PPy was estimated in the range of 70–80 wt%.
\nPPy/silver composites are composed of globules of about 1-μm diameter. This globular morphology is typical of PPy prepared with classical oxidants, such as iron(III) salts. The molecular structure of PPy produced was characterized by Fourier transform infra-red spectroscopy (FTIR) and Raman spectroscopy showing the same features as in PPy prepared with other oxidants. The morphology of silver nanoparticles was evaluated by transmission electron microscopy (TEM). Silver is present in particles of 50–100 nm size and occasionally larger polygonal crystals.
\nPPy/silver nanocomposites were used to coat cotton fabrics by in situ chemical oxidative polymerization using silver nitrate [39]. In a redox reaction, silver ions oxidize the pyrrole monomer and reduce to Ag0. The reduced silver was deposited on/into the polypyrrole/cotton matrix layer as nanoparticles. In the beginning, the cotton fabric was impregnated in a solution containing pyrrole. Silver nitrate was added into this solution and stirred. After completion of reaction, the cotton fabric was coated with a PPy/silver nanocomposites layer.
\nThe antimicrobial activity of PPy/silver-coated fabrics against E. coli and S. aureus bacteria was evaluated by the assessment test and agar diffusion test. The antimicrobial property of PPy/silver composites was measured by the clear zone of inhibition around the fabrics after incubation in agar plate method. Untreated cotton shows no antimicrobial activity against both bacteria. Moreover, the bacteria were grown over the surface. The PPy-coated cotton shows a small inhibition zone, whereas in PPy/silver composite-coated fabrics the inhibition zone was found to increase with increasing concentration of silver in the composites.
\nThe antibacterial activity of the PPy/silver composite-coated cotton fabrics was also quantified according to the AATCC 100-1999 procedure. The PPy/silver composite-coated cotton fabrics show a gradually increased bacterial reduction percentage over the contact time. The paper reported that the bacterial reduction reaches likely 100% within 6 h against E. coli and 12 h against S. aureus.
\nCommercially available antimicrobial fabrics already include fabrics composed of silver-coated fibres. Therefore, another possible approach could be to treat this kind of fabrics with PPy instead to synthesize silver nanoparticles during PPy deposition as previously reported.
\nIn a work [41], PPy deposition was carried out on cotton fabrics containing 10% of silver-coated fibres. PPy was synthesized at room temperature using ferric sulphate as oxidant. Antibacterial activity was evaluated following the AATCC Test Method 100–2012 against Gram-positive bacteria on textiles with different amount of PPy on fabrics with silver-coated fibres and pure cotton fabrics (without silver-coated fibres). A synergic biocidal effect between silver ions and PPy was observed. In fact, silver-containing fabrics used in this work alone does not guarantee a complete biocidal effect, but the addition of just 2 wt% of polypyrrole showed a bacterial reduction of 99%. On the other hand, excellent bacterial reduction (>99%) was found on pure cotton fabrics containing more than ~9 wt% of PPy, but the amount of PPy can be reduced to 5% in the presence of silver to reach the same level of efficiency.
\nFew papers reported the applications of PPy to man-made fibres for antimicrobial purposes. In particular, a study [42] was investigated where a polyethylene terephthalate (PET) fabric was coated with reduced graphene oxide (RGO) sheets, and then a PPy layer was deposited by in situ polymerization in order to cover RGO.
\nAntibacterial activity was assessed qualitatively against S. aureus (ATCC 25923) and E. coli (ATCC 25922) with AATCC 100-2003 standard method. PPy-coated sample showed antibacterial activity against both types of bacteria. The sample treated with RGO/PPy composite layer also showed excellent antibacterial activity against both bacteria that can be attributed to the existence of PPy with its antibacterial activity. No antibacterial activity was found on RGO-coated fabrics.
\nBacterial resistance to biocides, their inadequate activity, toxic effects on households and the environment and poor durability on textiles have become important issues of concern.
\nSome antimicrobial agents are commercially marketed as ‘eco-friendly’, such as Ultrafresh by Thomson Research Associates, Tinosan AM 110 (2,4,4′-Trichloro-2′-hydroxyl-diphenyl ether) by Ciba Specialty Chemicals, Sanitized AG by Clariant, Ecosy by Unitika, Utex by Nantech Textile Company Limited and Vantocil IB by Zeneca. However, investigating the chemistry behind these purportedly natural biocides, it is clear that they are not entirely natural.
\nAs a consequence, certain synthetic antimicrobial agents, such as Triclosan, have been banned by a number of leading retailers and governments in Europe, for their potential to cause skin irritation, non-biodegradable and bioaccumulation effects [43].
\nDue to these concerns, coupled with the high level of consumer awareness about clothing safety, many kinds of eco-friendly antimicrobial agents such as peroxy acids, chitosan and its derivatives or specific dyes have been developed for textiles.
\nIn the last years, significant progresses in the discovery of new compounds with antimicrobial activity, from natural products, were made. These substances may present an efficient antimicrobial effect, with safety, easy availability, non-toxicity to skin and environmental friendliness. Moreover, no resistance of pathogenic bacteria was reported towards these natural chemicals.
\nPlants have received interest as a major source of natural antimicrobials in nature [44, 45]. Materials extracted from different parts of plants such as bark, leaves, roots and flowers containing tannin, flavonoids and quinonoids but also alkaloids, saponins, terpenoids and phenolic compounds, with strong antimicrobial properties, have been investigated [46, 47].
\nEven essential oils, a mixture of a variety of aromatic compounds which can give cologne, can provide protection from a broad spectrum of microbes. The application of essential oils for antimicrobial effect on textiles has increased in recent times, due to their high efficiency, even if the real action against microbes is not clear.
\nA synergistic effect was noted, for example, for carvacrol and some hydrocarbon monoterpenes showing good antimicrobial properties: probably the hydrocarbons interacted with the cell membrane of the microbes and facilitated quick penetration of carvacrol into their cells. Similar effects were reported for eugenol/carvacrol and eugenol/thymol towards E. coli, suggesting that carvacrol and thymol disintegrated the outer membrane of E. coli, making it easier for eugenol to enter the cytoplasm. The advantages of synergy are the reduction of the concentration required to yield the same antimicrobial effect when compared with the sum of the purified components [48, 49].
\nNatural dyes, extracted from bark, leaves, roots, fruits, seeds and flowers, or from microorganisms such as fungi, algae and bacteria, have an inherent antimicrobial property due to the presence of different colouring materials such as tannin, flavonoids and quinonoids. Moreover, they offer a wide range of colours, are environmentally friendly and can be used in low-cost treatments with the additional benefit of colouring and confer antimicrobial activity in a single step [50].
\nNatural antimicrobial peptides, present in every living organism, are also promising natural candidates for antimicrobial textile applications. They are characterized by their small size (12–50 amino acids), the arginine and lysine residues responsible for their positive charge, and an amphipathic structure that interacts with microbial membranes. Some examples are daptomycin (Cubicin®, Cubist Pharmaceuticals), pexiganan, psoriazyna and plectasin NZ2114. Another efficient AMP is L-cysteine, successfully used to promote the biofunctionalization of wool and polyamide, conferring a durable antimicrobial finishing [51] to those fibres.
\nAmong the antimicrobial agents of natural origin, chitosan is gaining great interest in the last decades; in fact, chitosan and its derivatives appear to be the most effective natural antimicrobial agent on the market.
\nChitosan (2-amino-2-deoxy-(1->4)-b-D-glucopyranan) is a natural biopolymer, resulting from the deacetylation of chitin, constituting 20–30% of the exoskeleton of crustaceans.
\nIt is the second most abundant biopolymer in the world, following cellulose, meaning an easy availability at low cost [52]. Its natural origin makes it biodegradable, biocompatible, non-toxic and non-carcinogenic, that is, an eco-friendly product avoiding any environmental or hygienic issues.
\nThis biopolymer shows excellent film- and coating-forming properties when cast from organic acidic water solutions and, last but not least, it shows a strong antimicrobial activity against a wide spectrum of microorganisms, including fungi, algae and some bacteria.
\nThe antimicrobial action of chitosan is influenced by intrinsic factors and environmental conditions, such as the chitosan molecular weight and polymerization degree, its deacetylation degree, the pH of the medium and the microorganism type.
\nChitosan is considered to be both bacteriocidal and bacteriostatic although the exact action mechanism is not fully understood. The most acceptable models describe the interaction between positively charged chitosan groups and negatively charged microbial cell membranes due to electrostatic interactions. It promotes changes in the properties of membrane wall permeability causing internal osmotic imbalances and consequently inhibiting the growth of microorganisms. Even the hydrolysis of the peptidoglycans in the microorganism wall occurs, leading to the leakage of intracellular electrolytes as proteins, nucleic acids and glucose. Another proposed mechanism is the binding of chitosan with microbial DNA, which leads to the inhibition of the mRNA and protein synthesis via the penetration of chitosan into the nuclei of the microorganism, reaching the plasma membrane. A third mechanism is based on the excellent metal-binding capacity of chitosan due to the amine groups which are responsible for the uptake of metal cations by chelation, suppression of spore elements and binding to essential nutrients to microbial growth [53, 54].
\nDue to its diversified application fields, chitosan is a biomolecule with great potential. The antimicrobial activity was undoubtedly the most interesting application in recent years, leading to a wide application of chitosan, mainly in the field of food packaging and edible films, for biomedical and pharmaceutical purposes (drug delivery or tissue engineering), cosmetics and dermatological, agriculture, paper, enzyme immobilization and, of course, in textile field.
\nThe use of chitosan and its derivatives on fibres seems to be the more realistic prospect since this product does not provoke any immunological response.
\nBesides the biocidal properties of chitosan on textiles, it also has several other advantages considering the further colouration, because the amine group present readily reacts with dyes for successful dyeing/printing [55].
\nChitosan is mostly applied by the traditional pad-dry-cure process using chitosan/citric acid mixture mainly on cotton fabrics, even though other techniques have been used to impart antimicrobial property to fabrics. The use of binders with chitosan has also been reported [56] with the advantage that it can be applied to all manner of fabrics due to the presence of the binder.
\nComplexes based on chitosan and other biocidal agents have been studied to increase treatment efficiency and durability [57, 58]. Promising results were found with bivalent metal ions, such as Cu(II), Zn(II) and Fe(II), showing an antimicrobial effect much higher than the single components, due to the stronger positive charge after complexation [59], and with nanocapsules based on antibacterial polypeptide-grafted chitosan [60].
\nDespite some disadvantages in the use of chitosan in textile field, namely some temperature and pH activity dependence and poor handling, Eosy®, a commercial finishing product based on this biopolymer, and a composite fibre of chitosan and viscose, named Crabyon®, presenting a durable antimicrobial efficacy, are already available [61].
\nIn textile field, the most common way to apply chitosan to fabrics is by wet thermal curing, involving relatively high temperature with energy consumption, costs and possible fabric degradation; moreover, the addition of toxic reagents, such as glutaraldehyde, is requested as cross-linking agent.
\nIn recent research works, ultraviolet radiation in the presence of a suitable photoinitiator was proposed as an alternative process to graft chitosan molecules to textile fibres by radical process [62, 63]. In detail, in case of a cellulosic substrate such as cotton, the same cellulose molecule can be involved in the reaction by the formation of radicals, which can react with those formed on the chitosan molecule, conferring a strong fastness to the finishing. Moreover, UV grafting is a fast and eco-friendly process, carried out at room temperature, with lower cost than the traditional thermal process.
\nCotton, silk and synthetic fabrics were considered as substrates. Obtained results showed that chitosan UV curing yielded strong antimicrobial properties, reaching 100% m.o. reduction on all considered fabrics, as confirmed by antimicrobial tests carried out also on chitosan film. Moreover, low add-ons, 1–3% o.w.f., are enough to confer the desired property to the fabrics, so the hand properties of cotton or silk and the filtration capacity of synthetic fabrics are not compromised. In order to have a good treatment fastness, chitosan has to be diluted with acetic acid solution before spreading on fabrics and an impregnation time of 12 h at an ambient temperature or 1 h at 50°C is necessary before the curing to ensure a good penetration inside the fibres.
\nThe homogeneous distribution of chitosan on fabrics was confirmed by dyeing tests with an acid dye and by SEM analysis (Figure 2), which showed the optimal distribution of the finish on single fibre surface, while the presence of amino groups before and after the washing test, responsible for the antimicrobial activity, was revealed by ninhydrin assay and FTIR-attenuated total reflectance (ATR) spectra.
\nChitosan UV grafted to fibres: cotton (a), PET (b), PA (c) and silk (d).
Chitosan film was characterized by differential scanning calorimetry (DSC) and FTIR analysis. Data found are perfectly in agreement with literature data related to thermally cured chitosan, meaning that UV curing leads at the same polymer structure. Finally, on the FTIR-ATR spectra of treated cotton or synthetic fabrics, in comparison with untreated samples, the presence of the typical bands of chitosan is evident, showing its presence again.
\nChitosan was applied by UV grafting also to wool fibres, to confer a multifunctional finishing to the fabric, improving its value and application fields [64].
\nThe antimicrobial activity, reaching 67% E. coli reduction, was obtained by a surface modification of wool fibres with 2% grafted chitosan, preceded by an oxidative wool pre-treatment and 1-h impregnation at 50°C to enhance chitosan penetration in wool fibres. It was coupled to an improvement of wool dyeability towards acid dyes and some anti-felting properties with respect to the untreated substrate, while the treatment fastness to laundering depended on the used surfactant and no anti-pilling properties were conferred.
\nA semi-industrial scale-up of the process was carried out on cotton fabrics, following an encouraging preliminary laboratory research, on samples of reduced dimensions, aimed to optimize the main process parameters. To test the feasibility of the proposed treatment at larger scale, large white or dyed fabrics were impregnated by foulard with a commercial chitosan solution, significantly reducing the add-on to restrain the costs. Then, they were irradiated, both dried and wet, with a high-power UV lamp, in air.
\nObtained results confirmed the previous, laboratory scale, ones: a strong antibacterial activity with good washing fastness (99.9% microorganisms reduction after 30 washing cycles) was achieved by irradiation of the samples even wet and in air. It was obtained with a chitosan add-on percentage lowered till 0.3 wt% with a negligible affection of colour or hand properties of the fabric [65].
\nWastewater treatment is one of the major current applications of chitin/chitosan-based products due to their coagulating, flocculating and chelating properties.
\nEcological and health problems associated with heavy metals and pesticides accumulation in water and, as a consequence, through the food chain prompted the need for purification of industrial water in an efficient way.
\nThe ability of the free amino groups of chitosan to form coordinate/covalent bonds with metal ions is of great interest: chitosan in the form of a film or a powder or suitably grafted to an inert substrate can be used in metal ion complexing, in particular above its pKa value (about 6.5).
\nChitosan, carboxymethyl chitosan and cross-linked chitosan showed a strong efficiency in removing Cd2+, Cu2+, Hg2+, Ni2+ and Zn2+ ions from wastewater and industrial effluents [66–69].
\nChitosan was tested also as a sequestering agent for dye molecules, mainly present in wastewater from dyeing plants, showing a high efficiency towards different dye classes: acid, reactive, anionic and direct dyes [70–72].
\nCotton gauzes coated with chitosan using a UV-curing process were also tested, in static and dynamic conditions, as water filter for biological disinfection against both Gram-negative and Gram-positive bacteria. The material showed good antibacterial activity against E. coli, S. aureus and K. pneumoniae, in both static assessment and dynamic conditions: chitosan-treated gauze showed a high antimicrobial efficiency in few seconds of contact time. Results are of interest even if compared with those related to the same cotton gauze cationized with a quaternary ammonium salt. A certain pH sensitivity was found, but in all cases microorganism reduction never fell under 80% [73].
\nIt makes this composite a good candidate for its real use as biological filter.
\nThe presence of Gram-positive and Gram-negative bacteria and fungi is common on textiles, involving both synthetic and natural fibres. Due to their structure and chemical composition, textile products are prone to host microorganisms whose proliferation is responsible for diseases, unpleasant odours, colour degradation and deterioration of fabrics. Many of these microorganisms are pathogens, quite often related to nosocomial infections; therefore, the development of non-toxic processes for the preparation of antimicrobial textiles is gaining interest from both the academic researches and industry.
\nEmerging applications for biocidal finishes in textiles are required in different fields: sportswear, underwear, textile-based medical devices, home furnishing, filtration and depuration of water or air in crowded public areas. The required effect, depending on the application, can vary from the simple odour control to disease and infection control.
\nAmong the novel, natural and eco-friendly antibacterial finishing of textiles, a strong antibacterial finishing of textile substrates, with good fastness and stability, was obtained with both photo-grafted chitosan and polypyrrole coating on textiles.
\nMoreover, the morphology of PPy particles seems to effect antimicrobial performances, but the works, at the moment, were focused on particles not linked to a substrate. Further studies to improve PPy properties will appoint to produce PPy coating on the fabrics with particles having a designed shape.
\nIn another study not dealing with textile applications, polypyrrole-graft-chitosan (PPy-g-CS) copolymer was chemically synthesized and characterized [74]. PPy-g-CS showed an antibacterial activity stronger than chitosan and PPy alone, comparable with the antibiotics considered as reference. It suggests a synergic effect of polypyrrole-chitosan coating, exploitable in textiles.
\nAntimicrobial resistance is a global public health crisis. According to Public Health England [1], each year approximately 25,000 people die across Europe due to hospital-acquired infections caused by antibiotic-resistant and MDR bacteria such as Mycobacterium tuberculosis, Methicillin-resistant Staphylococcus aureus and multiresistant Gram-negative bacteria. Gram-negative infections include those caused by Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa [2]. Nevertheless, it is estimated that by 2050, the global yearly death toll will increase to 10 million. Accelerating emerge of antimicrobial resistance seriously threatens the effectiveness of treatments for pneumonia, meningitis and tuberculosis, in addition to diminishing prevention of infections acquired during surgeries and chemotherapies. The crisis of the antibiotic resistance requires urgent, coordinated action. Misuse and overuse of antibiotics must be controlled, implementation of new policies regarding prescriptions has to be internationally addressed; and development of new therapeutics is urgently required [1].
Félix d’Herelle, known as the father of bacteriophage (or phage) therapy [3], brought an evolutionary discovery of phages as therapeutics for various infections and conditions. Phage therapy was widely enforced in the 1920s and 1930s to combat the bacterial infections. However, in the 1940s, the newly discovered antibiotics replaced the phage therapy (except Russia, Georgia and Poland) [4].
The emergence of MDR bacteria prompted a renewal of the interest to the phage therapy as an alternative treatment to overcome a broad spectrum of resistant bacterial infections. Phage therapy and phage cocktails that contain a mixture of different bacteria-specific phages, drawn interest within molecular biology and modern medical research as potential antimicrobials that could tackle the crisis of antimicrobial resistance. Nonetheless, the phage therapy remains controversial due to its disadvantages such as bacteriophage resistance: bacteria-phage evolutionary arms race that could put a burden on a long-time application of phage therapy as an anti-infectious agent [5].
Phage therapy has many advantages, primary because phages are very specific (generally limited to one species) and easy to obtain as they are widely distributed in locations populated by bacterial hosts including soil and seawater, and they do not have any known chemical side effects like antimicrobials [6].
Understanding host-phage interactions and ‘the war between bacteria and phages’ are steps towards designing engineering ‘broad-spectrum phage’ that can overcome the limitations of phage therapy and potentially overcome a wide range of resistant bacterial infections [6].
Phages are obligate intracellular parasites that distinctively infect bacterial cells. Although phages are very specific to their host, generally limited to one species, they pose an enormous threat to bacteria as in some habitats they outnumber their hosts by nearly 10-fold number [7]. Phages are the most abundant, ubiquitous and diversified organisms in the biosphere [8, 9]. Phage-host interaction and fight for the survival led to the evolution of bacterial and viral genomes and, therefore, to the evolution of resistance mechanisms. Bacteria, continuously, evolve many molecular mechanisms, driven by gene expression to prevent phage infection. These evolving phage-resistance mechanisms in bacteria induce the parallel co-evolution of phage diversity and adaptability [10, 11]. The co-evolving genetic variations and counteradaptations, in bacteria and phages, drive the evolutionary phage-host arm race [11, 12].
Leigh Van Valen, an evolutionary biologist, metaphorised the co-evolutionary arm race and proposed the Red Queen hypothesis [13].
‘It takes all the running you can do, to stay in the same place’ the Red Queen says to Alice in Through the Looking-Glass.
The Red Queen hypothesis proposes that to survive, microorganisms must constantly adapt, evolve and thrive against ever-evolving antagonistic microorganisms within the same ecological niche [14].
Bacteria have developed various anti-phage mechanisms including non-adaptive defences (non-specific) and adaptive defences associated with Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) along with CRISPR-associated (Cas) proteins [7, 15, 16, 17, 18].
The non-specific adaptations (analogues to innate immunity in multicellular organisms) act as primary mechanisms to evade viral infection, and they include mechanisms that inhibit phage adsorption and prevent nucleic acid entry, superinfection exclusion systems, restriction-modification systems and abortive infection [7, 19].
On the other hand, the adaptive resistance (analogues to the acquired immunity in multicellular organisms) serves as a second line of defence, which is very efficient and phage-specific.
Interestingly, it was observed that the bacterial anti-phage mechanisms are generally present in a genomic array, known as ‘defence islands’ [20]. The ‘defence islands’ are enriched in putative operons and contain numerous overrepresented genes encoding diverged variants of antiviral defence systems. Moreover, scientific evidence and characteristic operonic organisation of ‘defence islands’ show that many more anti-phage mechanisms are yet to be discovered [21, 22, 23, 24].
Although bacteria have developed several resistance mechanisms against phages, phages can circumvent bacterial anti-phage mechanisms on the grounds of their genomic plasticity and rapid replication rates. These counterstrategies include point mutations in specific genes and genome rearrangements that allow phages to evade bacterial antiviral systems such as CRISPR/Cas arrays by using anti-CRISPR proteins and abortive infection by hijacking bacterial antitoxins, as well as escaping from adsorption inhibition and restriction-modification mechanisms [15, 16, 17, 18].
This chapter will comment on the genetic basis of bacterial resistance to phages and different strategies used by phages to evade bacterial resistance mechanisms.
Phage adsorption to host-specific receptors on the cell surface is the initial step of the infection and host-phage interaction. Depending on the nature of bacteria, whether it is Gram-positive or Gram-negative proteins, lipopolysaccharides, teichoic acids and other cell surface structures can serve as irreversible phage-binding receptors [19]. These receptors might be present in the cell wall, bacterial capsules, slime layers, pili or flagella [25].
Bacteria have acquired various barriers to inhibit phage adsorption, such as blocking of phage receptors, production of extracellular matrix (e.g. capsule, slime layers) and production of competitive inhibitors [26, 27, 28, 29, 30, 31]. The diversity of phage receptors in the host is influenced by co-evolutionary adaptations of phages to overcome these barriers [32]. This includes diversity-generating retroelements (DGRs) and phase variation mechanisms causing phenotypical differences within the bacterial colony [7, 33, 34].
Phase variation is a heritable, yet reversible process regulating gene expression in bacteria; genes can switch between a functional (expression) and a non-functional state leading to phenotypical variations within the bacterial population even when strains have identical genotype. Sørensen et al. [35] investigated the underlying resistance mechanism of Campylobacter jejuni (NCTC11168) to phage F336. They have discovered that phage F336 relies on the hypervariable O-methyl phosphoramidate (MeOPN) modification of capsular polysaccharides (CPS) for successful adsorption to the bacterial surface. Nevertheless, loss of MeOPN receptor on the bacterial cell surface due to phase variation in the cj1421 gene encoding the MeOPN-GalfNAc transferase (MeOPN transferase attaches MeOPN to GalfNAc and Hep side chains of CPS) results in phage resistance [35, 36].
DGRs are genetic elements diversifying DNA sequences and the proteins they encode ultimately mediating the evolution of ligand-receptor interactions. Error-prone DGRs and random mutations in the bacterial genes encoding cell surface receptors lead to the alternation and change in the structural composition of the phage receptors, making them non-complementary to the phage’s anti-receptors, known as receptor-binding proteins (RBP) [34] (Figure 1(1)).
Bacterial defence mechanisms preventing phage adsorption and phage’s counteradaptations. (1) Phage adsorption to a host-specific receptor site on a host cell surface. Bacterium evolves phage resistance by the modification of these cell surface receptors; phage is incapable of binding to the altered receptor. (2) Phage’s adaptation to these modifications through mutations in receptor-binding protein gene that leads to the co-evolution of bacterial genetic variation. Bacteria are also capable of producing proteins that mask the phage recognition site receptors (3 and 4), thus making the receptor inaccessible for phage adsorption [28, 29, 30, 31]. Image courtesy of springer nature: https://www.ncbi.nlm.nih.gov/pubmed/20348932.
Yet, phage’s replication is exceedingly error-prone, therefore causing many random mutations in the genes encoding the RBP or tail fibres. Phages also possess DGRs that mediate phage’s tropism by accelerating the variability in the receptor-coding genes through reverse transcription process [37]. The changes in the nucleotide sequence in the RBP-coding gene may ultimately lead to the adaptation to the modified receptor (Figure 1(2)), thus the ability to adsorb and infect the bacterial cell.
Unsurprisingly, bacteria also exhibit different strategies to block their receptors [28, 29, 30, 31].
Figure 1(4) demonstrates the findings from studies conducted on Staphylococcus aureus by Nordstrom and Forsgren [38]. Mutants of Staphylococcus aureus producing higher anticomplementary protein A were found to adsorb fewer phages than Staphylococcus aureus mutants with scarce of protein A, which had an apparent increased ability to adsorb phages [38]. These findings indicate that some bacteria, including Staphylococcus aureus, are capable of production of surface proteins that mask the phage receptors making them inaccessible for phage recognition and attachment (Figure 1(3)).
Receptors located on bacterial cell surface serve a vital role in bacterial metabolism; they may function as membrane porins, adhesions or chemical receptors [19]. Therefore, mutation or complete loss of the receptor might be lethal for bacteria. To inhibit phage adsorption, bacteria can produce surface molecules, such as exopolysaccharides.
Exopolysaccharides are extracellular polysaccharides acting as a physical barrier, composing slime or capsules surrounding bacterial cells that lead to inaccessible host receptors for efficient phage adsorption [39] (Figure 2). Studies conducted by Looijesteijn et al. [40] shown that exopolysaccharides produced by Lactococcus lactis function as external protection from phages and the cell wall destructing lysozyme, due to masked cell surface receptors [40].
Bacterial strategies to inhibit phage adsorption and phage strategies to access host receptors. Some bacteria are capable of the production of exopolysaccharides, which act as an outer shield, protecting a cell from the phage infection [28, 29, 30, 31]. If the phage does not possess any polysaccharide-degrading enzymes, it cannot access the host cell membrane receptor. However, some phages evolved mechanisms allowing them to recognise these extracellular matrixes and degrade them by the means of hydrolases and lyases [15, 16, 17, 18]. Image courtesy of Springer Nature: https://www.ncbi.nlm.nih.gov/pubmed/20348932.
Nevertheless, some phages evolved mechanisms allowing them to recognise these extracellular matrixes and degrade them by utilising hydrolases and lyases (Figure 2) [15, 16, 17, 18]. The polysaccharide-degrading enzymes allow phages to gain access to the receptor that may lead to the viral propagation. They are commonly present bound to the RBPs or exist as free soluble enzymes from previously lysed bacterial cells [41].
If phage bypasses primary antiviral strategies, it is now able to initiate infection by adsorption to a specific receptor site on a host cell surface through phage RBP [42, 43]. Upon interaction with the cell receptors, the phage injects its genetic material (single or double-stranded DNA or RNA) into the cytoplasm of the host. Depending on the nature of the phage and growth conditions of the host cell, it follows one of the two life cycles: lytic or lysogenic (Figure 3).
Lytic and lysogenic life cycles of a temperate coliphage λ that infects Escherichia coli [44, 45]. cos—cohesive sites: the joining ends that circularise the linear phage λ DNA. Image courtesy of Springer Nature: https://www.nature.com/articles/nrg1089.
In the lytic cycle, virulent phages degrade host’s genome leading to the biosynthesis of viral proteins and nucleic acids for the assembly of phage progeny. Eventually, the bacterial cell lysis, releasing a multitude of newly assembled phages, is ready to infect a new host cell [46].
In contrast, temperate phages might enter the lytic or lysogenic cycle, if the host cell exists in adverse environmental conditions that could potentially limit the number of produced progeny (Figure 3 demonstrates typical lifecycle of temperate phage using coliphage λ as an example) [44, 45]. In the lysogenic phase, repressed phage genome integrates into the bacterial chromosome as a prophage. This process causes the proliferation of prophage during replication and binary fission of bacterial DNA.
Prophage only expresses a repressor protein-coding gene. The repressor protein binds to the operator sites of the other genes and ultimately inhibits synthesis of phage enzymes and proteins required for the lytic cycle.
When the synthesis of the repressor protein stops or if it becomes inactivated, a prophage may excise from the bacterial chromosome, initiating a lytic cycle (induction) which leads to the multiplication and release of virulent phages and lysis of a host cell [44, 45].
If the phage remains in the nearly dormant state (prophage), the lysogenic bacterium is immune to subsequent infection by other phages that are the same or closely analogous to the integrated prophage by means of Superinfection exclusion (Sie) systems [47].
Sie systems are membrane-associated proteins, generally, phage or prophage encoded, that prevent phage genome entry into a host cell [47]. Figure 4 shows the role of Sie system (proteins Imm and Sp) in blocking phage T4 DNA entry into Gram-negative Escherichia coli. Despite successful attachment to the phage-specific receptor, phage DNA is directly blocked by Imm protein from translocating into the cytoplasm of the cell. Sp system, on the other hand, prevents the degradation of the peptidoglycan layer by inhibiting the activity of T4 lysozyme [26, 27, 28, 29, 30, 31, 48].
Superinfection exclusion systems preventing phage DNA entry in Gram-negative Escherichia coli. (a). Standard T4 phage: upon attachment to phage-receptor on the surface of the host cell, an inner-membrane protein aids the translocation of phage DNA into the cell’s cytoplasm. (b) Imm encoding phage T4: Imm protein directly blocks the translocation of the phage DNA into the cytoplasm of the cell. (c) Imm and Sp encoding phage T4: phage DNA is prevented from entering the cell’s cytoplasm by Imm; and Sp protein prevents degradation of the peptidoglycan layer by inhibiting the activity of T4 lysozyme [28, 29, 30, 31]. Image courtesy of Springer Nature: https://www.ncbi.nlm.nih.gov/pubmed/20348932.
The evolution of bacterial genomes allowed bacteria to acquire vast mechanisms interfering with every step of phage infection. In a case where a phage succeeded to inject its viral nucleic acid into a host cell, bacteria possess a variety of nucleic acid degrading systems such as restriction-modification (R-M) systems and CRISPR/Cas that protect bacteria from the phage invasion.
It has been reported that R-M systems can significantly contribute to bacterial resistance to phages [49].
R-M systems incorporate activities of methyltransferases (MTases) that catalyse the transfer of a methyl group to DNA to protect self-genome from a restriction endonuclease (REase) cleavage and REases, which recognise and cut foreign unmethylated double-stranded DNA at specific recognition sites, commonly palindromic. To protect self-DNA from the degradation, methylases tag sequences recognised by the endonucleases with the methyl groups, whereas unmethylated phage (nonself) DNA is cleaved and degraded (Figure 5) [26, 27, 50, 51, 52].
General representation of the bacterial restriction-modification (R-M) systems providing a defence against invading phage genomes. R-M systems consist of two contrasting enzymatic activities: a restriction endonuclease (REase) and a methyltransferase. REase recognises and cuts nonself unmethylated double-stranded DNA at specific recognition sites, whereas MTase adds methyl groups to the same genomic recognition sites on the bacterial DNA to protect self-genome from REase cleavage [50, 51]. Image courtesy of: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3591985/.
R-M systems are diverse and ubiquitous among bacteria. There are four known types of R-M within bacterial genomes (Figure 6). Their classification is mainly based on R-M system subunit composition, sequence recognition, cleavage position, cofactor requirements and substrate specificity [26, 27, 50, 51].
Four distinct types of restriction-modification (R-M) systems. (a) Type I R-M system is composed of three subunits forming a complex: hsdR (restriction), hsdM (modification) and hsdS (specificity subunit that binds to an asymmetrical DNA sequence and determines the specificity of restriction and methylation). Two hsdM subunits and one hsdS subunit are involved in methylation of self-DNA. On the other hand, two complexes of hsdR, hsdM and hsdS (where each complex consists of two hsdR, two hsdM and one hsdS subunit) bind to the unmethylated recognition sites on phage DNA and cleave the DNA at random, far from their recognition sequences. Both reactions—methylation and cleavage—require ATP. (b) Type II R-M system is composed of two distinct enzymes: palindromic sequence methylating methyltransferase (mod) and endonuclease (res) that cleave unmethylated palindromic sequences close to or within the recognition sequence. (c) Type III R-M system is formed of methyltransferase (mod) and endonuclease (res) that form a complex. Methyltransferase transfers methyl group to one strand on the DNA, whereas two methyltransferases (endonuclease complexes) act together to bind to the complementary unmethylated recognition sites to cleave the DNA 24–26 bp away from the recognition site. (d) Type IV R-M system contains only endonuclease (res) that recognises methylated or modified DNA. Cleavage occurs within or away from the recognition sequences [26, 27, 50, 51]. Image courtesy of: https://www.annualreviews.org/doi/abs/10.1146/annurev-virology-031413-085500?journalCode=virology.
Due to the diversity of R-M systems, phages acquired several active and passive strategies to bypass cleavage by REases. Passive mechanisms include reduction in restriction sites, modification and change of the orientation of restriction sites, whereas more specific, active mechanisms include masking of restriction sites, stimulation of MTase activity on phage genome or degradation of an R-M system cofactor (Figure 7) [15, 16, 17, 18].
Phage’s passive and active strategies to bypass restriction-modification (R-M) systems. (a) Phages that possess fewer restriction sites in their genome are less prone to DNA cleavage by the host restriction endonuclease (REase). (b) Occasionally phage DNA might be modified by bacterial methyltransferase (MTase) upon successful injection into a host cell. Methylated recognition sites on viral DNA are, therefore, being protected from the cleavage and degradation by REase, leading to the initiation of the phage’s lytic cycle. In addition, some phages encode their own MTase that is cooperative with the host REase; thus viral DNA cannot be recognised as nonself. (c) Some phages, for example, coliphage P1, while injecting its DNA into a host cell, it also co-injects host-genome-binding proteins (DarA and DarB) that mask R-M recognition sites. (d) Phages such as Coliphage T7 possess proteins that can mimic the DNA backbone. Ocr, a protein expressed by Coliphage T7, mimics the DNA phosphate backbone and has a high affinity for the EcoKI REase component, thereby interfering with R-M system. (e) In addition, some phages (e.g. Ral protein of Coliphage λ) can also stimulate activity of the bacterial modification enzyme in order to protect own DNA from the recognition by the bacterial REase as nonself. The peptide Stp encoded by Coliphage T4 can as well disrupt the structural conformation of the REase-MTase complex [15, 16, 17, 18]. Image courtesy of: https://www.nature.com/articles/nrmicro3096.
Fewer restriction sites in the evading genome lead to the selective advantage of this phage as its DNA is less prone to cleavage and degradation by the host REase (Figure 7a). Also, some phages incorporate modified bases in their genomes that may lead to successful infection of the host cell as REase may not recognise the new sequences in the restriction sites. A decrease in the effective number of palindromic sites in DNA or change in the orientation of restriction-recognition sites can affect R-M targeting. Alternatively, the recognition sites within the viral genome can be too distant from each other to be recognised and cleaved by the REase [15, 16, 17, 18, 53].
Interestingly, phage genome might be methylated by bacterial MTase upon successful injection into a host cell. Methylated recognition sites on viral genomes are therefore being protected from the cleavage and degradation by REase, leading to the initiation of the phage’s lytic cycle. Viral progeny remains insensitive to this specific bacterial REase until it infects a bacterium that possesses a different type of REase, in which case the new progeny will become unmethylated again and will, therefore, be sensitive to the R-M system of the cognate bacterium [28, 29, 30, 31].
The fate of the host cell chiefly confides in the levels of R-M gene expression and ultimate proportion of the R-M enzymes and their competition for the sites in the invading phage genome [52].
Furthermore, some phages encode their own MTase that is cooperative with the host REase, and thereby viral DNA cannot be recognised as nonself. Phages can also stimulate the activity of host modification enzymes that can rapidly methylate viral DNA, thus protecting it from the activity of REase.
Alternatively, phages can bypass R-M systems by masking restriction sites. For example (Figure 7c), coliphage P1, while injecting its DNA into a host cell, it also co-injects host-genome-binding proteins (DarA and DarB) that mask R-M recognition sites [53, 54].
As shown on an example of a Coliphage T7 (Figure 7d), some phages code for proteins that directly inhibit REase. Coliphage T7 possesses proteins that can mimic the DNA backbone. Ocr, a protein expressed by Coliphage T7, directly blocks the active site of some REases by mimicking 24 bp of bent B-form DNA, and it has a high affinity for the EcoKI REase component, thereby interfering with R-M system [53].
Lastly, phage-bacteria arm race allowed phages to gain capabilities of degrading necessary cofactors of R-M systems. For instance, coliphage T3 encodes S-adenosyl-l-methionine hydrolase that destroys an essential host R-M cofactor (the S-adenosyl-l-methionine). The removal of this necessary co-factor will lead to the inhibition of the REase, thereby successfully infecting the host cell [15, 16, 17, 18].
CRISPR along with CRISPR-associated (Cas) proteins is the type of adaptive heritable ‘immunity’ of bacteria, thus very specific and effective; and it is prevalent within the bacterial domain [55]. The CRISPR are DNA loci consisting of short palindromic repeats (identical in length and sequence), interspaced by segments of DNA sequences (spacer DNA) derived from previous exposures to phages. The spacer DNA sequences act as a ‘memory’, allowing bacteria to recognise and destroy specific phages in a subsequent infection. Genes encoding Cas proteins are adjacent to CRISPR loci [56].
Although some studies have suggested that CRISPRs can be used for pathogen subtyping [57], it has been found that CRISPR typing is not useful for the epidemiological surveillance and outbreak investigation of Salmonella typhimurium [58].
The CRISPR/Cas phage resistance is mediated in three-step stages: adaptation (acquisition), where spacer phage-derived DNA sequences are incorporated into the CRISPR/Cas system; expression, where cas gene expression and CRISPR transcription lead to pre-CRISPR RNA (pre-crRNA) that is then processed into CRISPR RNA (crRNA); and interference, during which the crRNA guides Cas proteins to the target (subsequently invading DNA) for the degradation. The cleavage of the target (proto-spacer) depends on the recognition of complementary sequences in spacer and protospacer [59, 60].
CRISPR/Cas systems have been classified into three major types: Types I, II and III, which are further divided into subtypes that require different types of Cas proteins. Although the CRISPR/Cas array is diverse among the bacteria and it is continuously co-evolving in response to the host-phage interactions, the defence activity in all three types of the CRISPR is comparable [21, 22, 23] Figure 8 illustrates the defence mechanisms in three distinct CRISPR/Cas arrays.
Image showing mechanisms of adaptation, expression and interference in three different types of CRISPR/Cas arrays. Type I and Type II CRISPR/Cas arrays rely on the protospacer adjacent motif (PAM), contained within phage nucleic acid, to ‘select’ the phage-derived protospacer. Next steps in the adaptation stage are similar in all three types; protospacer is incorporated by Cas 1 and Cas2 proteins into the bacterial genome at the leader end of the CRISPR loci to form a new spacer. In expression step, CRISPR loci are transcribed into pre-crRNA. The crRNA processing and interference stage is distinct in each type of the CRISPR/Cas system. In Type I, the multisubunit CRISPR-associated complex for antiviral defence (CASCADE) binds crRNA to locate the target, and with the presence of Cas3 protein, the invading target genome is degraded whereas in Type II, Cas9 protein is essential in the processing of the crRNA. TracrRNA recognises and attaches to the complementary sequences on the repeat region that is then cut by RNase III in the presence of Cas9. Lastly, in Type III, processing of pre-crRNA into crRNA is dependent upon the activity of Cas6. Mature crRNA associated with Csm/Cmr complex targets foreign DNA or RNA for the degradation [21, 22, 23]. Image courtesy of: https://www.nature.com/articles/nrmicro2577.
The Type II, CRISPR/Cas9, which was first identified in Streptococcus pyogenes, gained considerable interest within scientific studies as a precise genome editing tool. CRISPR/Cas9 system is unique; a single Cas 9 protein (in addition to prevalent Cas 1 and Cas 2) is involved in the processing of crRNA and destruction of the target viral DNA [56, 61].
In the adaptation stage, phage-derived protospacer (snippet of DNA from the invading phage) is incorporated into the bacterial genome at the leader end of the CRISPR loci. In expression phase, the Cas9 gene expresses Cas9 protein possessing DNA cleaving HNH and RuvC-like nuclease domains; CRISPR locus is then transcribed and processed into mature crRNA. Finally, in interference step, the complex consisting of Cas9, crRNA and separate trans-activating crRNA (tracrRNA) cleave 20 base pairs crRNA-complementary target sequence that is adjacent to the protospacer adjacent motif (PAM) [62].
To bypass CRISPR/Cas that has an incredibly dynamic rate of evolution, phages acquired array of strategies to succeed in propagation; this includes mutations in the protospacers or in the PAM sequences and expression of anti-CRISPR proteins, and even some phages encode their own functional CRISPR/Cas systems [15, 16, 17, 18, 63].
Phages can evade interference step of Type I and Type II CRISPR/Cas system by a single point mutation or deletion in their protospacer region or in the PAM sequence (Figure 9). Phages with single-nucleotide substitutions or deletions positioned close to PAM sequence can bypass the CRISPR/Cas activity and complete their lytic cycles; in contrast, phages with multiple mutations at PAM-distal protospacer positions do not [15, 16, 17, 18, 28, 29, 30, 31].
Evasion by mutation. Mutations in the phage protospacers or in the PAM sequences allow the phage to escape interference step of the CRISPR/Cas system that would lead to the degradation of the phage genome [15, 16, 17, 18]. Adapted image courtesy of: https://www.nature.com/articles/nrmicro3096.
In some circumstances, however, although the phage successfully evades CRISPR/Cas interference, the host cell may survive by the acquisition of new spacer sequences (derived from invading phage) into their own CRISPR/Cas system. This new spacer provides the bacterium with an accelerated spectrum of phage resistance [15, 16, 17, 18].
Prophages integrated within Pseudomonas aeruginosa possess genes that encode anti-CRISPR proteins directly suppressing CRISPR/Cas-mediated degradation of the phage genome (Figure 10). According to Wiedenheft [64], these proteins might interrupt CRISPR RNA processing by preventing mature crRNA from binging to the crRNA-guide complex or by preventing the assembled crRNA-guided complex from interacting with target substrates through binding to it [64].
Anti-CRISPR proteins expressed against CRISPR subtype I-F systems. Temperate phages such as Pseudomonas aeruginosa possess genes encoding anti-CRISPR proteins that directly interfere with the bacterial CRISPR/Cas system [15, 16, 17, 18]. Adapted image courtesy of: https://www.nature.com/articles/nrmicro3096.
Prophages do not only contribute to bacterial resistance to invading phages, they can also encode proteins that contribute to bacterial virulence and antimicrobial resistance [58, 66].
Bacteria can also resist phages by possessing phage-inducible chromosomal islands (PICI) which prevent phage replication. Nevertheless, phages evolved their genomes to overcome this very specific antiviral strategy. For example, Vibrio cholerae ICP1 phages possess their own CRISPR/Cas systems that inactivate PICI-like elements (PLE) in Vibrio cholerae (Figure 11). Studies conducted by Naser et al. [67] have shown that phage CRISPR arrays have evolved by the acquisition of new spacers targeting diverse regions of PLEs carried by Vibrio cholerae strains. Furthermore, the addition of the new spacers within phage CRISPR/Cas loci enables the phages to expand their ability to counter PLE-mediated phage defence of diverse Vibrio cholerae strains [67].
Phage-encoded CRISPR/Cas systems in Vibrio cholerae ICP1 phages. Upon adsorption and injection of viral genome into a host cell, phage crRNAs and CRISPR/Cas complexes are expressed and target phage-inducible chromosomal island (PICI) in the host genome; in the Vibrio cholerae, they are termed as PICI-like elements (PLE). If the spacers within phage CRISPR locus are complementary to the bacterial PLE, the CRISPR machinery is then able to specifically target this genetic element and inactivate it, leading to the viral propagation. However, in the absence of such targeting, phage CRISPR/Cas system can acquire new spacers to evolve rapidly and ensure effective targeting of the PLE to restore phage replication [15, 16, 17, 18, 65]. Adapted image courtesy of: https://www.nature.com/articles/nrmicro3096.
Abortive infection (Abi) systems promote cell death of the phage-infected bacteria, inhibiting phage replication and providing protection for bacterial populations [68].
Abi systems require both toxins and antagonistic antitoxins. Antitoxins are proteins or RNAs that protect bacterial cell from the activity of toxins in a typical cell life cycle, whereas toxins are the proteins encoded in toxin-antitoxin locus that disrupt cellular metabolism (translation, replication and cell wall formation), causing cell death. During an infection, the expression of the antitoxin encoding gene is suppressed, leading to the lethal activation of the toxin [69]. Figure 12 illustrates the mechanism of Abi systems in Escherichia coli [70].
Abortive infection (Abi) systems in Escherichia coli. The Rex system is a two-component Abi system. A phage protein-DNA complex (formed during phage replication) activates the sensor protein RexA, which in turn activates RexB. RexB is an ion channel that causes depolarisation of the bacterial membrane leading to cell death [28, 29, 30, 31]. Image courtesy of Springer Nature: https://www.ncbi.nlm.nih.gov/pubmed/20348932.
Interestingly, phages evolved an array of tactics to circumvent Abi systems. This includes mutations in specific phage genes and encoding own antitoxin molecules that suppresses bacterial toxin [15, 16, 17, 18]. Figure 13 provides a broad overview of the strategies employed by the phages to by-pass Abi systems.
Escaping abortive infection mechanisms. (a) In a typical cell life cycle, antitoxins protect bacterial cell from the activity of toxins. (b) During phage infection, the expression of antitoxin encoding gene is suppressed, leading to the lethal activation of the toxin. (c) Mutations in certain phage genes can lead to escaping Abi systems activity, thereby a successful viral propagation without killing the host cell. (d) Some phages encode molecules that functionally replace the bacterial antitoxins, thus suppressing toxin activity and avoiding host cell death [15, 16, 17, 18]. Image courtesy of: https://www.nature.com/articles/nrmicro3096.
Bacteria-phage interaction is therefore very complex, and it is crucial to understand the molecular basis of this interaction and how bacteria and phages ‘fight’ each other. It has been reported that Anderson Phage Typing System of Salmonella Typhimurium can provide a valuable model system for study of phage-host interaction [71].
The rapid emergence and dissemination of MDR bacteria seriously threaten global public health, as, without effective antibiotics, prevention and treatment of both community- and hospital-acquired infections may become unsuccessful and lead to widespread outbreaks.
Carbapenems and colistin are antibiotics of last resort, generally reserved to treat bacteria which are resistant to all other antibiotics. Until not long ago, colistin resistance was only described as chromosomal, however, in 2016 Liu et al. reported the emergence of the first plasmid-mediated colistin resistance mechanism, MCR-1, in Enterobacteriaceae [72]. Furthermore, the increasing occurrence of colistin resistance among carbapenem-resistant Enterobacteriaceae has also been reported [73]. This is of significant concern as infections caused by colistin and carbapenem-resistant bacteria are very challenging to treat and control, as the treatment options are greatly limited or non-existent. Thus, the discovery and development of alternative antimicrobial therapeutics are the highest priorities of modern medicine and biotechnology.
Phages should be considered as great potential tools in MDR pathogens as they are species-specific (specificity prevents damage of normal microbiota), thus harmless to human; they have fast replication rate at the site of infection, and their short genomes can allow to further understand various molecular mechanisms implied to ‘fight’ bacteria. In addition, this understanding can enable scientists to ‘manipulate’ viral genomes and engineer a synthetic phage that combines the antibacterial characteristics of multiple phages into a single genome.
The escalating need for new antimicrobial agents attracted new attention in modern medicine, proposing several potential applications of phages as antibacterial therapeutics including phage therapy, phage lysins and genetically-engineered phages.
Phage therapy utilises strictly lytic phages that have bactericidal effect. As phages are host-specific, ‘phage cocktails’ containing multiple phages can broaden range of target cells. Nevertheless, selection of suitable phages is at the paramount to the successful elimination of clinically important pathogens, and it includes avoidance of adverse effects, such as anaphylaxis (adverse immune reaction) [74].
In order to hydrolyse and degrade the bacterial cell wall, phages possess lysins.
The spectrum of efficiency of natural lysins (derived from naturally occurring phages) is generally limited to Gram-positive bacteria; however, recombinant lysins have shown an ability to destabilise the outer membrane of Gram-negative bacteria and ultimately lead to rapid death of the target bacteria [74].
Bioengineered phages have the potential to solve inherent limitations of natural phages such as narrow host range and evolution of resistance. Various genetic engineering methods have been proposed to design phages with extended antimicrobial properties such as homologous recombination, phage recombineering of electroporated DNA, yeast-based platform, Gibson assembly and CRISPR/Cas genome editing [75].
Engineering of synthetic phages could be tailored to enhance the antibiotic activity, to reverse antibiotic resistance or to create sequence-specific antimicrobials [74].
The antagonistic host-phage relationship has led to the evolution of exceptionally disperse phage-resistance mechanisms in the bacterial domain, including inhibition of phage adsorption, prevention of nucleic acid entry, Superinfection exclusion, cutting phage nucleic acids via restriction-modification systems and CRISPR, as well as abortive infection.
Evolvement of these mechanisms has been induced by constant parallel co-evolution of phages as they attempt to coexist. To survive, phages acquired diverse counterstrategies to circumvent bacterial anti-phage mechanisms such as adaptations to new receptors, digging for receptors and masking and modification of restriction sites and point mutations in specific genes and genome rearrangements that allow phages to evade bacterial antiviral systems such as CRISPR/Cas arrays, as well as mutations in specific genes to bypass abortive infection system. Conclusively, the co-evolving genetic variations and counteradaptations, in both bacteria and phages, drive the evolutionary bacteria-host arm race.
Besides, accumulating evidence shows that phages contribute to the antimicrobial resistance through horizontal gene transfer mechanisms. Indeed, many bacterial strains have become insensitive to the conventional antibiotics, posing a growing threat to human; and although in the past, western counties withdrew phage therapy in response to the discovery of therapeutic antibiotics, now, phage therapy regains an interest within the research community. There are apparent advantages of phage therapy, such as specificity, meaning only target bacteria would encounter lysis, but not healthy microbiota inhabiting human’s system. Additionally, ‘phage cocktails’, containing multiple bacteria-specific phages, could overcome the issue of phage-resistance as phages do adapt to these resistance mechanisms. However, ‘phage cocktails’ would require large numbers of phages that would have to be grown inside pathogenic bacteria in the laboratory, putting laboratory staff and the environment at risk.
Alternatively, building up the understanding of host-phage interactions and ‘the war between bacteria and phages’ could potentially lead to defeating antimicrobial resistance by designing synthetic phages that can overcome the limitations of phage therapy.
Dr Manal Mohammed is funded by a Quinton Hogg start-up award, University of Westminster.
abortive infection capsular polysaccharides clustered regularly interspaced short palindromic repeats crispr RNA diversity-generating retroelement deoxyribonucleic acid multidrug-resistant O-methyl phosphoramidate methyltransferase protospacer adjacent motif phage-inducible chromosomal island PICI-like element receptor-binding protein restriction endonuclease restriction-modification ribonucleic acid superinfection exclusion trans-activating crRNA
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