Quorum quenching quandary: resistance to antivirulence compounds

Abstract

Quorum sensing (QS) is the regulation of gene expression in response to the concentration of small signal molecules, and its inactivation has been suggested to have great potential to attenuate microbial virulence. It is assumed that unlike antimicrobials, inhibition of QS should cause less Darwinian selection pressure for bacterial resistance. Using the opportunistic pathogen Pseudomonas aeruginosa, we demonstrate here that bacterial resistance arises rapidly to the best-characterized compound that inhibits QS (brominated furanone C-30) due to mutations that increase the efflux of C-30. Critically, the C-30-resistant mutant mexR was more pathogenic to Caenorhabditis elegans in the presence of C-30, and the same mutation arises in bacteria responsible for chronic cystic fibrosis infections. Therefore, bacteria may evolve resistance to many new pharmaceuticals thought impervious to resistance.

Exploiting Quorum Sensing To Confuse Bacterial Pathogens

“…In any event, it seems likely that inhibition of LasR during growth on adenosine would result in selective pressure to develop resistance to the inhibitor in order to maximize growth. In agreement with this hypothesis, a transposon mutant screen of P. aeruginosa grown on adenosine in the presence of the QS inhibitor C-30 successfully yielded mutants with increased resistance to C-30 (241). The various mutants were found to carry transposon insertions in either mexR or nalC, both genes which encode repressors of the multidrug resistance efflux pump MexAB-OprM.…”

“…aeruginosa also requires a functional LasR QS system in order to grow on adenosine (343), which has been postulated to be a physiologically relevant carbon source during growth in vivo (241), although it should be mentioned that the relatively high frequency of lasR mutant isolates recovered from chronic CF patients (332) contradicts this assumption unless adenosine utilization has become LasR independent in these strains. In any event, it seems likely that inhibition of LasR during growth on adenosine would result in selective pressure to develop resistance to the inhibitor in order to maximize growth.…”

“…The various mutants were found to carry transposon insertions in either mexR or nalC, both genes which encode repressors of the multidrug resistance efflux pump MexAB-OprM. Importantly, mutation of mexR had no effect on bacterial virulence but did abolish the protective effects of C-30 treatment during infection in C. elegans (241). Interestingly, mutations in mexR and nalC have been found in clinical isolates of P. aeruginosa (344), and these isolates were resistant to C-30 (241), suggesting physiologically relevant pressures for mutations that could increase inhibitor resistance during growth in vivo.…”

“…Diverse sets of furanone compounds have been generated by chemical synthesis (237,238), yielding inhibitors tested most frequently and rigorously on P. aeruginosa quorum sensing and on the V. fischeri LuxR protein heterologously expressed in E. coli, where compounds C-30 and C-56 (Table 3) were the most effective inhibitors (134,237,(239)(240)(241)(242)(243). More recently, additional synthetic schemes have led to new varieties of furanones, but their inhibitory properties remain relatively untested (244,245).…”

Inhibition ofSteptococcus mutansbiofilm formation by extracts ofTenacibaculumsp. 20J, a bacterium with wide-spectrum quorum quenching activity

“…He et al [23] indicate that the furanone acts through an unknown mechanism not dependent of the production of the QS-signal AI-2 since it affected not only S. mutans but also the luxS mutant strain. In any case, the toxicity described for these molecules, causing the rapid death of fish [44], and the development of resistance to furanone-based QS inhibitors [45] exclude the use of these molecules as antimicrobial agents.…”