Despite the discovery of antibiotics, the battle against bacteria is so far in their favor, specifically because bugs are able to develop a superstructure named biofilm, to resist and to survive in the environment. Nosocomial infections, a major health problem, are due at 80% to biofilm‐associated infection, and Staphylococcus aureus is the leading bacteria species in this domain. Moreover, the antimicrobial resistance of this bacterial community is accentuated when it is formed by superbugs such as methicillin‐resistant S. aureus (MRSA). In this chapter, the mechanism and the physiology of S. aureus biofilm as well as their consequences in the clinical domains are described. To complete the vision on S. aureus biofilms, some “anti‐biofilm” strategies will be highlighted.
- Staphylococcus aureus
- antibiotic resistance
- anti‐biofilm strategies
Discoveries in microbiology and the setup of aseptically processes in medical science allowed the possibility of high‐level surgery over the last century, with the hope of a safe healing. In return, major problems have appeared as nosocomial infections due to bacterial biofilm formations on medical devices [1, 2]. Despite the multiplication of surgical procedures in order to get as close as sterile environment, bacterial contamination remains an important risk. Bacteria could indeed acquire antibiotic resistances and an emergence of multidrug resistant strains is observed [3, 4]. Moreover, the most alarming is that bacteria with regular sensitivity to antibiotics are even able to develop a strategy to survive: the formation of a strong community named biofilm [1, 2, 5]. Biofilm‐associated infections represent 80% of nosocomial infections, and
Biofilm is defined as a multicellular lifestyle, an organized structure built by almost all bacterial species. Even if the term “biofilm” has been used for more than 60 years, the understanding of this structure started but recently. Fossilized biofilms of 3.5 billion years have been discovered and highlight the hypothesis that biofilm is a survival strategy always used by microorganisms since the dawn of time . Scientists have recently understood that bacteria are not always living as free cells in nature; on the contrary, most of the time, bacteria build a real social life in a resistant community surrounded by a matrix composed of polysaccharides, extracellular DNA, proteins, lipids and other components [1, 2]. Biofilm is present on biotic or abiotic surface and bacteria embedded inside are 10–1000 times more resistant to conventional antibiotics than free‐floating bacteria according to the strains, the molecule applied and the model of study [7–9]. Life cycle of biofilm is nowadays well‐described. First, bacteria adhere on a surface and they enhance different mechanisms to irreversibly be attached. Then, the program of biofilm starts with a maturation of the multicellular structure. To complete this cycle, dispersion of swimming cells occurs under specific conditions [1, 2, 7–9]. However, the key of biofilm mechanism is the initiation that leads bacteria to form a biofilm and only under specific conditions. This trigger of biofilm mechanism is still an important question. Survival would be the answer, thus biofilm structure allows bacteria to resist to any types of environmental stress including UV, lack of nutrients and presence of antimicrobials [1, 2, 7–9].
All these characteristics lead to major problems in industries as well as in the medical domain. In industry, for example, the presence of multispecies biofilms has a high impact on the processes or on the production and results in high costs.
In the medical domain, numerous difficulties to treat biofilm‐associated infections are described: resistance to antibiotics and to immune system, spread of infection, sepsis shock and surgical risks to remove infected implant or tissues [1, 6, 8].
Here after, to better understand the strength of
2. Biofilm life cycle
Different steps of biofilm life cycle have been well‐described through the study of different bacterial species: reversible adhesion, irreversible attachment, maturation and dispersion [5, 13] (Figure 1). First, active bacteria can turn from “swimmers” to “stickers” on a support. A surface is supposed to always be in favor of adhesion because of the prediction that organic substances will concentrate on a surface and microorganisms will easily adhere and be protected from outsider challenges. Adhesion will dependent on the species of bacteria, surface composition, environmental factors, and essential gene products . Microorganisms could adhere on inert or biotic surfaces. Most of the time, interaction between bacteria and abiotic surface involves nonspecific interactions as opposed to active interaction between microorganisms and live tissues . The surface conditioning is quite important through various physiochemical parameters: hydrophobicity, chemical composition of the material, surface energy, eletrostatic charges, temperature, surface roughness and in the case of biotic adhesion: serum and tissue protein adsorption [14, 15]. Hydrophobicity increases bacterial adhesion in most cases [15, 16]. In some environmental conditions, macromolecules adsorption could form a “film” neutralizing excessive charges and surface free‐energy facilitating bacteria and surface proximity. It was shown that pH parameters influence
As far as
2.1. Attachment on a surface
In any case, the life of a biofilm starts by an adhesion. The latter is reversible but can turn irreversible. Indeed, under specific conditions, events of irreversible attachment tend to increase and lead to the formation of a biofilm. In fact, irreversible attachment is the first step to the maturation of a future biofilm.
At the beginning, adhesion is the fortunate meeting between a good conditioned surface and a bacterium. In any environment, microorganisms can randomly get close to the surface or be attracted by chemotaxis involving their motility system . Very recently, the ability for motility was observed for
A surface could be attractive or repulsive for bacteria according to different parameters described above including hydrophobic and electrostatic interactions, hydrodynamic forces and temperature. Hydrophobicity is considered the most important. Bacteria could adhere on a biotic or abiotic surface thanks to the involvement of specific bacterial surface molecules such as the surface protein autolysin or the teichoic acids, altering the physicochemical properties of the bacterial surface rather than mediating the attachment via specific, receptor‐mediated interactions .
In the human body,
2.2. Communication between bacteria
During biofilm formation, Agr quorum‐sensing system is repressed to stop the expression of
Other regulators have been identified such as Rbf which is involved in
In conclusion, production of surfactant molecules dependent of quorum‐sensing system appears to be a general mechanism for the biofilm structuring as well as for the detachment of many bacteria. In the specific
The maturation of biofilm is based on the development of the multicellular structure (Figure 1). Biofilm growth is controlled by the increase of bacterial mediators, the slowdown of metabolism and cell cooperation. Maturation starts when bacterial cells induce the biofilm program and create an intercellular aggregation through the production of a “slime” commonly named matrix. The latter sticks bacteria one to each other as well as on surface. The matrix is composed of exopolysaccharides (EPS), proteins and extracellular DNA (eDNA) and is responsible for biofilm maturation that is the result of an organized community construction. This specific 3‐dimensional structure appears as a typical mushroom‐like shape containing water or fluid channels formed thanks to a disruptive process . Paradoxically, maturation in the construction of the community needs also disruption events. Fluid‐filled channels are vital in delivering nutrient into biofilm deeper layers . This kind of structure is species‐specific.
Exopolysaccharides are the first molecules discovered in biofilm matrix. In staphylococci, the most described adhesive biofilm molecule is the polysaccharide intercellular adhesion (PIA) or poly‐N‐acetylglucosamine (PNAG) and represents the major part of the staphylococci biofilm‐forming extracellular matrix . PIA has an important role in the biofilm structure and the biofilm‐associated infections [40, 41]. Introducing a positive charge in the environment of the bacterial cell surface which is negatively charged, PIA works like a glue sticking the cells together by electrostatic interaction . PIA is encoded by
Numerous specific proteins could be substitute for PIA in biofilm formation as proteins are now recognized as essential for biofilm structure, such as the following proteins: Aap (accumulation associated protein), extracellular matrix binding protein (Embp), protein A, fibrinogen‐binding proteins (FnbpA and FnbpB) or
All these results underline the importance of the surfactants in biofilm maturation. Phenol‐soluble modulins (PSM) are surfactant peptides found in both
Amyloid proteins have also been revealed as important for biofilm structure, bringing stability to the matrix . These protein fibers could bind the extracellular DNA. PSMs play also a role as inert fibrils in biofilm, acting as a solid bond, waiting for better conditions to induce their dissociation and promote biofilm dispersion [53, 54]. Bap another cell wall bound surface protein [25, 55–57], involved in adhesion, is also required for biofilm maturation and infection of bovine mammary glands [20, 45]. This protein is a real sensor, responding to environmental conditions (like calcium concentration), and Bap is also a scaffold protein forming amyloid‐like aggregates at low calcium concentration and under acidic pH .
Under an organized construction, biofilm maturation is based on development and disruption events. Thus, PIA‐degrading enzymes (PIAse) are supposed to contribute to biofilm maturating but they have never been found in staphylococci . Anyway other proteases could have an important role in staphylococci biofilm maturation as proven by strains showing PIA‐independent biofilm formation . Those proteases are regulated mostly by SarA and more rarely by Agr, but so far no experiments have demonstrated direct evidence for their role on biofilm development or protease‐mediated biofilm detachment.
The third important element of matrix composition is extracellular DNA (eDNA). DNA, a polyanionic molecule present in biofilm matrix, is described as a ligand able to link to other molecules present in the matrix such as teichoic acids or PIA. Therefore, DNA has a role in biofilm structure. This presence is based on the involvement of cell death: DNA released from lysed bacteria also called eDNA has a critical involvement during initial attachment and maturation. An increase of cell lysis influences biofilm formation through the Cid proteins [59–61]. Indeed, regulators like CidR which controls autolysis are involved in biofilm development and the formation of the tower mushrooms shapes . Extracellular DNA appears through the bacterial programmed cell death and through the expression of
In conclusion, scientists have realized how important it is to have precise knowledge of the mechanisms involved in the biofilm extend matrix or in the detachment steps to be able to develop anti‐biofilm strategies. However, biofilms are also formed by four set of cells: some with an aerobic or fermentative growth, some dormant or dead . This cell heterogeneity within the biofilms has to be kept in mind in the search of anti‐biofilm therapy.
Disruptive processes are vital for biofilm structure and disruption allows the detachment of single cells or large bacteria cluster from biofilm in case of good environmental conditions or in case of expansion of the biofilm (Figure 1). This dispersion has important consequences in biofilm‐associated infections as it leads to systemic dissemination. It is well known now that detached cells from biofilm could lead to endocarditis or sepsis .
Disruption is based on mechanical forces as well as the interruption of the production of the biofilm material and production of enzymes and surfactants that are considered as detachment factors able to destroy the matrix. Agr quorum‐sensing system involved in biofilm formation and extracellular protease activity are required to control biofilm dispersal molecules [28, 32, 52]. Expression of
Nucleases, the enzymes degrading extracellular DNA are also necessary. The human DNaseI degrades staphylococcal biofilms . Staphylococcal thermonuclease
Other factors, involved in dispersion, have been described such as bacteriophages which have been revealed as important for biofilm development, especially in dispersal stage . Even proteases like Aur metalloprotease and Slp serine protease have been shown to be responsible of dispersal movement .
In conclusion, biofilm life cycle starts under the impulse of a stress response (e.g., starvation) and bacteria attach on a surface where cell proliferation is more favorable. A monolayer is formed, and some specific genes are expressed inducing the production of microcolonies. Quorum‐sensing system acts as a supervisor, and biofilm is formed in a well‐organized structure.
3. Physiology of biofilm
Biofilms seem to be the best strategy for bacteria to survive to any kind of environmental stress. The detection of stress and thus the response needs to be fast enough to survive under those conditions. Therefore, the rapid process of activation of the biofilm program is crucial for the bacteria.
3.1. Program on/off
As described for stress response, the setup of inducible processes is based on the differential expression of an important number of genes [68, 69]. Biofilm bacteria cells are physiologically different from free cells . Indeed, the different steps as adhesion and immobilization need the expression of various genes. More important, the communication between bacteria (quorum‐sensing system) controls many metabolic systems and leads to regulation of many genes. The production of the quorum‐sensing molecules as an endogenous signal leads to changes according to the detected concentration. Environmental clues trigger genetic and physiological changes also called biofilm transition. As previously described, the matrix is the plinth of biofilm development and is responsible for many processes in the biofilm program. Moreover, biofilm cells show a general downregulation of their metabolism underlining the slow growing cell or the lack of oxygen due to the biofilm structure, like during fermentation. An upregulation of the urease and the arginine deiminase pathway to limit the side effects of the acidic pH during anaerobic growth was also observed in biofilm structure . All those adaptations participate to a general biofilm setup process. The differential gene expressions also lead to antibiotic resistance mechanism. In
Biofilm program is a temporary response to stress conditions and this process is able to turn off quite quickly when conditions are more favorable for the bacteria.
3.2. Interactions with the environment and survival strategy
Bacteria have the extraordinary ability to survive in any harsh conditions, and as recently discovered, this is due to their capacity to form biofilm. Many environments can be a source of stress for bacteria.
Nitrite stress also induces PIA expression, responsible for the major part of the matrix composition . In fact, induction or repression of biofilm formation is due to a balance of concentration of specific nutrients or stress. For example, NO is necessary for biofilm formation until its concentration starts to be too high. Thereafter, NO is involved in the dispersion of the biofilm . It has also been observed that low oxygen, even anaerobic state, like in the heart of the biofilm, increases PIA expression .
In human body, the lack of nutrients (e.g., iron, carbon source, etc.) or oxygen, the presence of the immune system or even the antimicrobial molecules are felt by the bacteria as stresses and could induce biofilm program. In
In nature, many bacteria live under nutrient‐limited conditions, lack of oxygen and under many other dangers like humidity, osmotic pressure and mechanical forces. Biofilm through the presence of the matrix protect all the embedded bacteria from all those environmental variations and pressures.
3.3. Interactions with the host immune cells
During bacterial infection, host immune cells are the defenders of the organism. Through mechanisms such as phagocytosis or release of bactericidal components, these cells are able to fight and neutralize planktonic
PMNs are the first line of defense in bacterial infections. These cells can phagocyte planktonic bacteria and release bactericidal components such as reactive oxygen species or enzymes . Contrary to the dogma,
In parallel to PMNs response, a macrophage response is also triggered during
The most recent studies concerning interactions between
Concerning interactions between
S. aureus biofilm‐associated infections and antibiotic treatments
S. aureus biofilms are responsible for different types of infection
Different bacteria are involved in infections associated with biofilm development in immunocompromised patients or medical devices. Sadly, the most famous example is
Biofilm formation is linked to various staphylococcal diseases such as endocarditis, osteomyelitis, skin and soft tissues infections, urinary tract infection, nasal colonization and cystic fibrosis complications as well as implant‐associated infections [97–99]. In most of the case, the production of biofilm favors the chronicity of
S. aureus biofilm‐associated infections are more resistant
Biofilms have shown unbreakable structures resistant to antibiotics and many other molecules or environmental stresses. Many hypotheses have been tested to explain this incredible natural invincibility. First, the intrinsic structure of biofilm supposes that antimicrobials could not penetrate inside the biofilm. This hypothesis has been revealed unlikely for most of the antibiotics as the biofilm structure is composed with many water channels. A second hypothesis is based on the fact that the biofilm matrix can accumulate antibiotic‐degrading enzymes, and in consequence, antibiotics are quickly destroyed . Then, scientists underline the fact that microorganisms have a very slow metabolism in the biofilm preventing most of the kinetic responses involved in the antibiotic mechanism. The use of antibiotics targeting more specifically those slow growth bacteria was not more successful, even combined with antimicrobial drugs that could target active bacteria present in the biofilm population, known to be heterogenic . Persister cells can also be present in this heterogeneous population and can withstand high concentration of antimicrobial drugs.
Nowadays, it seems that the natural resistance of biofilms comes from the induction of specific biofilm mechanisms . Stress responses, as biofilm formation, lead to the changes of many gene expressions which increase the antimicrobial resistance. Nutrient starvations are now known to favor antibiotic tolerance .
Biofilm is the perfect example of an adaptive resistance, not due to a genetic mutation that could be transferred to daughter cells, even if the bacteria proximity in the biofilms increase horizontal transfer gene or mutation that could lead to intrinsic resistance .
4.3. Current treatment of
S. aureus biofilm
Firstly, antibiotics can have an inhibitive effect on the formation of biofilm. It is related to the capacity to inhibit the attachment and the initial growth of the biofilm. A recent study specifically evaluated the inhibition of
The second situation concerns the efficiency of antibiotics on formed/mature biofilm. The sessile community is already organized and persisters can be present. In this case, antibiotic efficiency is defined through the measure of the minimal biofilm eliminating concentration (MBEC) via the use of the Calgary Biofilm Device . MBEC for
The difference between bMIC and MBEC is probably due to a lack of penetration/diffusion of antibiotics inside the biofilm, even if this statement still stays controverted. Indeed, a decreased penetration of antibiotics has been observed in
With regards to this, the combination of antibiotics appears as an interesting solution for an effective treatment. Susceptibility test revealed that rifampin, but also vancomycin and fusidic acid were the most interesting constituent of antibiotic combinations active against the staphylococcal biofilms . In an innovative
The efficiency of antibiotic monotherapies or bi-therapies was most of the time evaluated through the use of
Globally, trying to prevent the biofilm formation appears as the most interesting way to fight this kind of infection. In case of full‐formed biofilm infections, using a combination of high‐dosed antibiotics containing rifampicin and/or daptomycin seems to be the best option.
In addition to the difficulties to treat biofilm‐associated infection, there is also the important delay necessary to spot them. The emergency of finding a technical approach to detect biofilm in the analysis laboratories is huge. Some biomarkers have been searched, especially thanks to qPCR (quantitative polymerase chain reaction) techniques. For example,
5. Future strategies to fight against biofilm formation
Nowadays biofilm existence cannot be ignored anymore. Scientist community has to find new ways of fighting this bacterial social network as to avoid biofilm formation, or to weaken its intrinsic resistance, to disrupt biofilm or to kill bacteria embedded in this structure as detailed by Bjarnsholt et al.  and summarized in Figure 3.
5.1. Prevention by antiadhesive or anticommunication molecules
Prevention will always be the best strategy to fight against biofilm formation. Moreover, inhibiting the biofilm formation, bacteria stay under “planktonic” form and are much more susceptible to antimicrobial or immune system molecules, and therefore easier to eliminate. Prevention has to be used as a prophylactic strategy, especially for devices implant during surgery . The idea is to avoid bacterial adhesion on material. As a consequence, some anti‐adhesive surfaces are developed to be used in implant manufacturing . For example, titan implants coated with gentamicin showed a local action and a short period release fighting
To conclude, the conceptualization of molecules interfering with signals responsible for biofilm program induction could be imagined and this could lead to the presence of only free‐floating bacteria that are more susceptible to antibiotics.
In case the biofilm prevention fails, other strategies have to be developed. Weakening strategies are based on the idea of avoiding the biofilm properties set up, being efficient only on biofilm in formation not on mature biofilm . Targets of this strategy are virulence factors, communication molecules or specific metabolic pathway involved in biofilm maturation. In
Molecules interrupting the production or assembly of amyloid fibers could consequently destabilize biofilm structure. The compound (-)‐epi‐gallocatechine gallate (EGCG) used to fight against amyloid peptides involved in Alzheimer's and Parkinson's diseases is also active to inhibit
It will be interesting to develop other vaccines or drugs which target virulence factors that enhance biofilm formation.
5.3. Biofilm disruption
As for “weakening” strategies, targeting Agr quorum‐sensing system in
Another target to disrupt biofilm is the matrix, using for example, PIA‐degrading enzymes. Two matrix polymers in staphylococcal biofilms poly‐N‐acetylglucosamine and eDNA could be targeted for their destruction by dispersin B and DNaseI, respectively. Dispersin succeeded in detaching pre‐formed
To eradicate a pre‐form biofilm is the last chance and this strategy remains the most difficult to fathom. Many molecules have been tested but they have to respect many criteria like the non‐cytotoxicity and the non‐pro‐inflammatory effects. Promising molecules are the “anti‐biofilm” peptides inspired by animal antimicrobial peptides (AMPs) which have anti‐inflammatory effects and are efficient to destroy Gram‐positive or Gram‐negative bacteria at very low concentrations [73, 133]. They have also shown their ability to act in synergy with conventional antibiotics, avoiding the use of too high concentrations of each molecule .
After the revolutionary discovery of antibiotics, the medical community thought that the battle against microorganisms was won. However, the fight had just begun as bacteria can develop resistant structure named biofilm among other strategies.
We thank Kevin Delaitre for careful proofreading.
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