RT Journal Article SR Electronic T1 Evidence for complex interplay between quorum sensing and antibiotic resistance in Pseudomonas aeruginosa JF bioRxiv FD Cold Spring Harbor Laboratory SP 2022.04.05.487235 DO 10.1101/2022.04.05.487235 A1 Sikdar, Rakesh A1 Elias, Mikael H. YR 2022 UL http://biorxiv.org/content/early/2022/04/06/2022.04.05.487235.abstract AB Quorum sensing (QS) is a cell-density-dependent, intercellular communication system mediated by small diffusible signaling molecules. QS regulates a range of bacterial behaviors, including biofilm formation, virulence, drug resistance mechanisms, and antibiotic tolerance. Enzymes capable of degrading signaling molecules can interfere in QS - a process termed quorum quenching (QQ). Remarkably, previous work reported some cases where enzymatic interference in QS was synergistic to antibiotics against Pseudomonas aeruginosa. The premise of combination therapy is attractive to fight against multidrug-resistant bacteria, yet comprehensive studies are lacking. Here we evaluate the effects of QS signal disruption on the antibiotic resistance profile of P. aeruginosa by testing 222 antibiotics and antibacterial compounds from 15 different classes. We found compelling evidence that QS signal disruption does indeed affect antibiotic resistance (40% of all tested compounds; 89/222), albeit not always synergistically (not synergistic for 48% of compounds with an effect (43/89)). For some tested antibiotics, like sulfathiazole and trimethoprim, we were able to relate the changes in resistance caused by QS signal disruption to the modulation of the expression of key genes of the folate biosynthetic pathway. Moreover, using a P. aeruginosa-based Caenorhabditis elegans killing model, we confirm that enzymatic QQ modulates the effects of antibiotics on P. aeruginosa’s pathogenicity in vivo. Altogether, these results show that signal disruption has profound and complex effects on the antibiotic resistance profile of P. aeruginosa. This work suggests that combination therapy including QQ and antibiotics should not be discussed globally but rather in case-by-case studies.IMPORTANCE Interference in bacterial Quorum Sensing (QS) is a promising approach to control microbial behavior. Of particular interest is the potential of this strategy to reduce biofilms and virulence of antibiotic resistant strains. Interestingly, several studies report synergistic interactions between antibiotic treatments and interference in QS. However, it is unclear whether this is a generality, let alone the molecular mechanisms underlying the observed synergies. Here, we provide a comprehensive description of combination treatment in the model organism, opportunistic human pathogen P. aeruginosa. Screening > 200 antimicrobials, and combining them to QS signals and disruption strategies, we show that there is no systematic synergy between these approaches in vitro, as well as in vivo, in a C. elegans infection model. Altogether, this work show that QS has complex connections to the antibiotic resistance profile of P. aeruginosa, and that combination treatment should not be discussed globally, but rather in case-by-case studies.Competing Interest StatementMHE is the co-founder, former Scientific Advisory Board member, and equity holder of Gene&Green TK, a company that holds the license to WO2014167140 A1, FR 3068989 A1, FR 19/02834. MHE has a patent No. 62/816,403. These interests have been reviewed and managed by the University of Minnesota in accordance with its Conflict-of-Interest policies. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.