Resistance to Quorum-Quenching Compounds

Abstract

c Bacteria have the remarkable ability to communicate as a group in what has become known as quorum sensing (QS), and this trait has been associated with important bacterial phenotypes, such as virulence and biofilm formation. Bacteria also have an incredible ability to evolve resistance to all known antimicrobials. Hence, although inhibition of QS has been hailed as a means to reduce virulence in a manner that is impervious to bacterial resistance mechanisms, this approach is unlikely to be a panacea. Here we review the evidence that bacteria can evolve resistance to quorum-quenching compounds. Infectious diseases are the leading cause of death (1), and all antibiotics fail (2); therefore, it is imperative to develop novel ways to fight microbial infections. Here we review the use of chemicals that interfere with cell communication and investigate the likelihood that bacteria will evolve resistance to these compounds.QS and QQ. Bacteria use secreted chemicals as signals for a variety purposes, including virulence and biofilm formation. When the compounds build to a threshold concentration and trigger gene expression, the signals are known as quorum-sensing (QS) signals. Examples of well-studied QS signals include acylhomoserine lactones, autoinducer 2, and peptide signals, but many other signals, such as indole, exist (3). In addition to signals, signal synthases, signal receptors, signal response regulators, and regulated genes (QS regulon) are key components of any QS system (4). For example, LuxI-type enzymes are signal synthases which synthesize acylhomoserine lactones. In addition, LuxR-type regulators are receptor proteins for the autoinducer signals, and signalreceptor binding is responsible for the expression of QS regulons. Since numerous compounds that inhibit QS have been identified, since QS is linked to virulence, and since inhibition of QS does not usually affect growth (in rich medium), it has been reasoned that inhibition of QS may be an effective means of reducing pathogenicity that is not subject to the usual resistance mechanisms of bacteria (1,(5)(6)(7)(8). Inhibition of QS is also known as quorum quenching (QQ) and is a form of antivirulence.The well-known examples (9) of QQ compounds include lactonases/acylases that degrade the N-(3-oxoctanoyl)-homoserine lactone (HSL) autoinducers, synthase inhibitors, like analogues of anthranilic acid that block synthesis of quinolone signals (10), and receptor inhibitors, such as brominated furanones (11). In addition, low concentrations of azithromycin, ceftazidime, and ciprofloxacin (antibiotics) inhibit QS in Pseudomonas aeruginosa (12). Also, among the thousands of drugs approved for clinical use, the anthelmintic drug niclosamide is a QQ compound (13); this drug reduces surface motility, biofilm formation, and production of the secreted virulence factors elastase, pyocyanin, and rhamnolipids. The rhizosphere bacterium Stenotrophomonas maltophilia produces cis-9-octadecenoic acid, which is a QQ compound that reduces violacein production by Chromoba...

Quorum sensing enhancement of the stress response promotes resistance to quorum quenching and prevents social cheating

“…Through the adenosine screening, C-30-resistant mutants were identified that have mutations in the mexR and nalC genes. Both genes encode transcriptional repressors of the mexAB-OmpR operon, which encodes a multidrug resistance efflux pump that we showed is able to efflux C-30 when its expression is de-repressed (Maeda et al, 2012;García-Contreras et al, 2013a).…”

Mathematical Modelling of Bacterial Quorum Sensing: A Review

“…Although they observed "resistance", they did not validated their data experimentally. However, simultaneously, a group provided evidence that resistance to QQ is indeed possible (Maeda et al 2012;García-Contreras et al 2013). Anand et al (2013) used an experimentally validated computational model of LuxI/LuxR QS to study the effects of using inhibitors individually and in combination.…”

Can resistance against quorum-sensing interference be selected?

“…One attractive feature of such therapies is that it was hypothesized that unlike growth inhibition-based therapies, anti-virulence therapies should be impervious to resistance (Rasmussen and Givskov, 2006;Bjarnsholt et al, 2010;Rasko and Sperandio, 2010). However, recently it was demonstrated that the generation and selection of resistance against quorum quenchers (QQs) occurs as readily as it does for antibiotics, under conditions in which growth is directly coupled to QS (García-Contreras et al, 2013b;Kalia et al, 2013;Maeda et al, 2012). Experimentally, these conditions are achieved by growing the bacterial pathogen Pseudomonas aeruginosa with adenosine as sole carbon source, as its catabolism is tightly dependent on a functional LasR QS system (Heurlier et al, 2005) and as it is metabolized internally by the QS-proficient bacteria.…”