Interference in Bacterial Quorum Sensing: A Biopharmaceutical Perspective

Abstract

Numerous bacteria utilize molecular communication systems referred to as quorum sensing (QS) to synchronize the expression of certain genes regulating, among other aspects, the expression of virulence factors and the synthesis of biofilm. To achieve this process, bacteria use signaling molecules, known as autoinducers (AIs), as chemical messengers to share information. Naturally occurring strategies that interfere with bacterial signaling have been extensively studied in recent years, examining their potential to control bacteria. To interfere with QS, bacteria use quorum sensing inhibitors (QSIs) to block the action of AIs and quorum quenching (QQ) enzymes to degrade signaling molecules. Recent studies have shown that these strategies are promising routes to decrease bacterial pathogenicity and decrease biofilms, potentially enhancing bacterial susceptibility to antimicrobial agents including antibiotics and bacteriophages. The efficacy of QSIs and QQ enzymes has been demonstrated in various animal models and are now considered in the development of new medical devices against bacterial infections, including dressings, and catheters for enlarging the therapeutic arsenal against bacteria.

Keywords: antibioresistance; bacterial virulence; biofilm; medical devices; phage resistance; quorum quenching enzymes; quorum sensing (QS); quorum sensing inhibitors.

Figure 1

Quorum sensing and quorum quenching in a wounded tissue. The skin usually harbors a natural and commensal flora which is not pathogenic (Upper Left). When a wound or a lesion occurs, bacteria colonize the wounded tissue and further develop being in a favorable environment (Upper Right). While growing, bacteria produce communication molecules (autoinducers). If the molecules are not degraded (Bottom Left), bacteria can synchronize their behavior to secrete virulence factors and produce biofilms which may prevent efficiency of antibiotic or phage therapy. The wound is infected. If the autoinducers are degraded (Bottom Right) bacteria do not synchronize their behavior and remain harmless and defenseless. The wound remains colonized but no infection occurs.

Figure 2

Representation of autoinducer molecules. The left circle represents autoinducing peptides used by Gram-positive bacteria such as Staphylococcus spp., Clostridium spp., Enterococcus faecalis (Monnet et al., 2016). The right circle gives an overview of the different molecules used in Gram-negative quorum sensing: acyl homoserine lactones (AHLs) (Schuster et al., 2013), quinolones (PQS), 4-hydroxypalmitate methyl ester (3-OH-PAME) (Flavier et al., 1997), fatty acids (DSF) (Zhou et al., 2017), epinephrine, and norepinephrine (Kendall and Sperandio, 2007). In the middle, the different forms of AI-2, a furanosyl diester, used by both Gram-positive and Gram-negative bacteria are depicted (Chen et al., 2002).

Figure 3

Representation of quorum quenching agents. Quorum sensing inhibitors, mainly acting against AHL or AI-2-based QS, are depicted in the orange circle (Tang and Zhang, 2014). Antibiotics such as azithromycin can be used as QSI at sub-inhibitory concentrations (Swatton et al., 2016). Purple circle represents the QQ peptides used to inhibit Gram-positive QS (Singh et al., 2016). Blue circle represents molecules used to scavenge AIs such as cyclodextrins or derivatives (Morohoshi et al., 2013) and antibodies scavenging AHL (Fab RS2-1G9) or AIP (AP4-24H11) (Park et al., 2007). Green circle depicts QQ enzymes that disrupt AHLs (SsoPox, Pvdq, and AiiA), the quinolone PQS (HOD) and AI-2 signals (QQ-2) (Fetzner, 2015).