Natural products represent the major source of approved drugs and still play an important role in supplying chemical diversity as well as new structures for designing more efficient antimicrobials. They are also the basis for the discovery of new mechanisms of antibacterial action. In this regard, a large number of substances, mainly extracts from natural sources, have been obtained in order to identify their anti-virulence activity. In recent years, there is an increase in the study of anti-virulence natural product derivatives. Different targets have been proposed as a solution to the serious problem of bacterial antibiotic resistance. Inhibition of bacterial quorum-sensing systems has been one of the most studied; however, there are other mechanisms involved in virulence regulation, damage to the host and bacterial survival, which suggests that there are another good targets such as bacterial secretion systems, biofilm formation, two-component systems, flagellum, fimbriae, toxins and key enzymes. Within the natural products, the main anti-virulence compounds are phenolic in nature, so that the next chapter describes and analyzes the relationship between chemical structure and activity of the main phenolic compounds reported.
- quorum sensing
- antibiotic resistance
Since their introduction in the middle forties, antibiotics had been extensively used for the treatment of infectious diseases, producing remarkable results and saving millions of lives worldwide ; nevertheless, bacteria are very dynamic organisms able to interchange genes by several mechanisms including conjugation, transformation and transfection via bacteriophages . In addition, they usually replicate at high rates and hence have the ability to evolve quickly and adapt to strong selective pressures; this combined with the self-prescription, inadequate prescription by some physicians (e.g., to treat viral diseases) and their improper use by patients who do not complete the recommended treatment scheme has derived in an alarming situation since to date antibiotic resistance (including multiresistance and panresistance) is a common trend in most of hospital-acquired infections and is becoming more common in community-acquired ones [2, 3]. In fact, the situation is so delicate that recently, the OMS warned that if the current trends are still observed, then by the year 2050 we will enter the post-antibiotic era and previously treatable infectious diseases will cause more deaths than other important diseases such as cancer .
Hence, the discovery of new antibiotics as well as the development of alternative approaches to combat bacterial infections is urgently needed ; among such new approaches are the inhibition of bacterial antibiotic resistance mechanisms, the utilization of non-antibiotic bactericide agents such as bacteriophages, the repurposing of clinically approved drugs, and the inhibition of bacterial virulence . For the first approach, already successful examples can be found in the clinic; by instance, the co-utilization of clavulanic acid (an inhibitor of β-lactamases) and amoxicillin is commonly administrated ; and current research is focused on the utilization of broad spectrum anti-resistance compounds such as those inhibiting multidrug efflux pumps . Regarding the second approach, it was recently demonstrated that some anticancer drugs such as 5-fluorouracil , mitomycin C  and cisplatin  have remarkable antibacterial properties, while bacteriophages had been used in east European countries for the treatment of diverse bacterial infections, and currently, its utilization in the occidental medicine is being proposed [11, 12]. Finally, targeting bacterial virulence instead of their viability is a concept that had derived in several publications, mostly centered in the inhibition of master virulence regulators such as quorum-sensing (QS) systems, which allow several Gram-negative and Gram-positive bacteria to coordinate the production of several virulence factors, once a high population density is reached (Figure 1A). Indeed, initially, it was claimed that this approach will be impervious to the generation of resistance since
As mentioned previously, QS is a master regulator of the production of several bacterial virulence factors, such as: exoproteases that degrade connective tissue such as elastase and alkaline protease (collagenase), phenazines that promote the generation of reactive oxygen species, siderophores that facilitate iron uptake, toxins that disrupt cellular processes and exopolysaccharides that form phagocytosis-resistant capsules and participate in the generation of the biofilm matrix  (Figure 1C).
Another key factor for the development of chronic infections and colonization of surfaces is the formation of biofilms, which is the main way the bacteria are found in nature . These structures consist of multicellular communities enclosed in a matrix which makes them extremely resistant to antibacterial agents (Figure 1B) . They also provide robust niches that allow the bacteria to protect themselves from environmental fluctuations and against the immune system, which drastically reduces the effectiveness of antimicrobial therapy .
Since for many pathogenic bacteria QS is the main regulator of expression of bacterial virulence factors , its disruption has been the main anti-virulence strategy investigated to date . However, another alternative that has also been reported is the
TCS are response regulators which are formed by a protein localized in the cytoplasmic membrane called histidine kinase sensory protein (HKSP), which acts as an environmental sensor that is activated in ATP-dependent way (Figure 1D) . HKSP then activates a response regulator protein (RRP) found in the cytoplasm which is responsible for recognizing DNA sequences that modulate the expression of genes involved in various functions such as chemotaxis, porin expression and expression of virulence factors among others (Figure 1D) . An important feature is that TCRs have not detected in mammalian cells, so there are a suitable specific target to treat bacterial infections .
The curli (Figure 1E) is the major protein component of the extracellular matrix and is mainly produced by enterobacteria to aid in the formation of three-dimensional structures such as biofilms . Curli fibers belong to a growing class of fibers known as amyloid fibers, which are also involved in host cell adhesion and invasion, and are also strong inducers of host inflammatory response . The structure and biogenesis of curli are unique among bacterial fibers and represent an excellent anti-virulence target .
The type III secretion system (T3SS) also known as the injectisome is a multiprotein apparatus that facilitates the secretion and translocation of toxins or effector proteins from the bacterial cytoplasm directly to eukaryotic cells (Figure 1F) [26, 27]. It is highly conserved in most Gram-negative pathogens, but its presence is not a necessary condition for bacterial survival
Motility and recognition surfaces are key factors for the dispersal and colonization of new niches by bacteria . For that, the flagellum and the fimbriae are target structures suitable for anti-virulence molecules [28, 29]. The flagella (Figure 1G) are multiprotein complexes based on flagellin, which rotate allowing bacterial displacement in aqueous media , while fimbriae (Figure 1H) are extracellular protein structures mainly constituted by pilin, which start in the plasma membrane, cross the cell wall and extend around the cell. These structures allow the adhesion of bacteria mainly to epithelial cells .
Another important virulence factors are the sortase enzymes (cysteine transpeptidases) (Figure 1I), which are used by Gram-positive bacteria to display proteins in cell surface, such as glycoproteins , and they can also attach to proteins in the cross-bridge peptide of the cell wall or link other proteins together to form pilin . The phenomenon of protein deployment is essential for the development of virulence factors and promotes nutrient acquisition, adhesion and immune system evasion . Because surface proteins play a fundamental role in microbial physiology and are frequently virulence factors, sortase enzymes are a very important target .
Reports related to the study of natural products as anti-virulence molecules had increased in the last decade. Their powerful attack against bacterial infections without promoting resistance and the elimination of antibiotic-resistant strains are the most attractive features of this kind of compounds. Among natural products with anti-virulence activity, those derived from plants with anti-QS and antibiofilm activity are the most common . Phenolic compounds are secondary metabolites present in plants, which are crucial in many aspects of their lives, especially during the interactions with the environment, since they are used in the defense of plants against bacterial pathogens. Similarly, compounds of phenolic type are the major metabolites with anti-virulence properties described so far, and specifically, the flavonoids are the main representatives .
Most of the biologically active reported phenolic compounds have chemical structures with previously identified antimicrobial, antioxidant and anticancer activity. Similarly, for some of them their participation in the regulation of various physiological functions in plants and animals is well known. In recent years, the anti-virulence properties of phenolic compounds are being unravel, and most of the cases depend on the compound concentration and the bacterial system in which the phenolic compounds can exhibit bactericidal or anti-virulence effects. In the next chapter, we discuss studies of phenolic compounds derived mainly from plant species, starting with those that are better characterized and that have more anti-virulence reported properties. We focus on the relationship between their structures and their activity.
2. Phenolic compounds anti-virulence
2.1. Epigallocatechin gallate and related compounds
It is well documented that this kind of compounds has antimicrobial, antioxidant, anti-inflammatory, hypocholesterolemic and cancer-preventive properties [34, 35]. The
At the same concentration,
However, using sublethal concentrations, it has been found that EGCG significantly decreased the expression of virulence genes that regulate the expression of cytolysins, gelatinase and serine protease in
For the case of
Dental plaque is a complex biofilm that allows the survival and development of
EGCG at sublethal concentrations also inhibits motility and biofilm formation of
It is worth noting that to date there are no studies to investigate its structure-activity relationship, so it is not yet known which parts of the structure are critical to their anti-virulence effects. However, for the (−)
2.2. Cinnamaldehyde and related compounds
The antibiofilm properties of CN have been widely documented; for example, in
Various cinnamaldehyde analogs were also evaluated against
The CN also has inhibitory activity on biofilm formation in a methicillin-resistant
Among the cinnamaldehyde-related molecules, the
The QS inhibitory activity of CA and FA also was evaluated in
2.3. Coumarin and related compounds
Similarly, the presence of characteristic functional groups promotes the effective inhibition of virulence factors, as in the case of the furocoumarins ,
2.4. Curcumin and related compounds
The major constituent of turmeric (
The secretion of sortase A (SrtA) a surface protein in
The antibiofilm activity of CUR against uropathogens such as
Diverse virulence factors in
2.5. Eugenol and related compounds
In a methicillin-resistant (MRSA) and methicillin-sensitive (MSSA) S. aureus at subinhibitory concentration, EG eradicates pre-established biofilms and inhibited the colonization of this bacteria in a rat middle ear model, decreasing biofilm in biomass, cell viability and the expression of biofilm-related genes (icaD, sarA and seA), resulting in a low accumulation of polysaccharides and poorly adhesion of cells within biofilms . The biofilm eradication effect of EG was mediated by two mechanisms: bacterial lysis within biofilms and by the disruption of cell-to-cell connections, hence dismantling the biofilm organization, which can be attributed to the hydrophobic and the lipophilic nature of their chemical structure .
The biofilm formation and biofilm-related genes in
Moreover, derivatives of EG
2.6. Long-chain phenols
Long-chain phenols are a group of metabolites which have extensively studied antitumor, antimicrobial and antioxidant activities; they are also of great interest to the industry because they are used to manufacture different chemicals . Also, different long-chain phenols reported have different anti-virulence properties.
Our research group identified a mixture of four
Similarly, the antibiofilm activity of
Furthermore, although mixtures of such compounds have shown anti-virulence activity, separation is laborious and costly, so their chemical syntheses become an attractive alternative. In this regard, AA synthetic (6-oxa isosteres) C: 11-C: 16 (Figure 7E) showed inhibition of TCS (KinA/SpoOF and NRII/NRI) . Interestingly, AA with alkyl chains outside this range are not active . Likewise, for this activity, the presence of the carboxyl group is important, as the C:12 and C:14 completely lose their effect, and the presence of phenolic OH partially restores it. Long-chain phenols are a group of natural products with great structural diversity, which represent an important potential source of molecules with anti-virulence activity.
2.7. Quercetin and related compounds
Various biological activities including anti-cancer, antibacterial, hepatoprotective, anti-inflammatory and antiviral activities have been attributed to flavonoids ; moreover, recent studies have shown that various flavonoids also have anti-virulence activity.
In addition, antibiofilm activity in
Furthermore, it has been shown that the
2.8. Resveratrol and related compounds
Since plants produce RV, this metabolite was identified as the active compound with inhibitory activity against biofilm formation in
Compounds related to RV, the
The RV and its oligomers, namely
2.9. Salicylic acid and related compounds
Several studies have demonstrated that SA has inhibitory activity in the motility and production of extracellular virulence factors in the opportunistic pathogenic bacteria
The biofilm formation in
Compounds related to SA, the
Other important hydroxy benzoic acid with a numerous reports of anti-virulence properties is
The inhibitory activity showed by these compounds may be related to some of their structural features, since different reports mentioned that in the active phenolic compounds, the basic skeleton remains the same, the basic skeleton remains same, but the number and positions of the hydroxyl groups on the aromatic ring and the type of substituents provide different biological properties [120–122]. Also, SA,
3. Conclusion and future perspective
An important feature of the anti-virulence molecules is that they may be less prone to promote the emergence of resistance than conventional antibiotics. At the moment, phenolic compounds represent the largest number of natural products with anti-virulence-reported activity and whose main target has been the inhibition of QS and biofilms. However, it has also been found that they can directly inhibit some of virulence factors such as sortases, curli, type III secretion system (T3SS), fimbriaes and two-component regulatory systems. It should be noted that most of the phenolic compounds represent structures already known, several of which have been subject to different pharmacological studies and some are even part of the international pharmacopeia and are active ingredients of herbal medicines.
Moreover, although QS is considered the main regulator of bacterial virulence, this is still part of a complex network of interconnected components including several environmental regulation systems and QS-independent virulence factors. Also, the direct
Given the growing public health problem worldwide derived by the emergence of bacterial multiresistance to antibiotics, the development of suitable anti-virulence therapies is presented as a viable strategy to provide a solution to this problem; moreover, we are in the decisive years that will dictate the implementation of these kind of strategies, this is occurring in a period of resurgence of the interest in natural products activities in which phenolic compounds have a fundamental role.
This work was supported by grants from Scientific Development Projects for Solving National Problems/CONACyT Mexico no. 2015-01-402. N-MC research is supported by the CONACYT PhD Grant 376049 and M-PL by the CONACYT PhD Grant 302218. R-GC research is funded by SEP-CONACYT 152794 and by PAPIIT-UNAM IA201116. I-CJ research is supported by Fideicomiso-COLPOS 167304 and Cátedras-CONACyT program.
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