Evidence for Complex Interplay between Quorum Sensing and Antibiotic Resistance in Pseudomonas aeruginosa

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12 Scopus citations

Abstract

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 as 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 19% of compounds; 43/222). For some tested antibiotics, such as 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 confirmed 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 be discussed not globally but, rather, in case-by-case studies.

Original languageEnglish (US)
JournalMicrobiology Spectrum
Volume10
Issue number6
DOIs
StatePublished - Nov 2022

Bibliographical note

Funding Information:
This work was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award no. R35GM133487. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Funding Information:
We thank Eliana Drenkard and Frederick Ausubel at the Massachusetts General Hospital for providing us with Pseudomonas aeruginosa strain PA14, Bonnie Bassler and Julie Valastyan at Princeton University for providing us with Pseudomonas aeruginosa AHL synthase mutant strains SM51, SM52, and SM53, Ryan Hunter at the University of Minnesota for providing us with Pseudomonas aeruginosa isolate strain CI19, Barry Bochner at Biolog, Inc., for helping us set up the experimental protocol with Biolog Phenotype MicroArrays, and Aric Daul at the Caenorhabditis Genetics Center (CGC) at the University of Minnesota for providing us with Caenorhabditis elegans strain SS104 and Escherichia coli strain OP50. This work was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award no. R35GM133487. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
Copyright © 2022 Sikdar and Elias.

Keywords

  • Pseudomonas aeruginosa
  • antibiotic resistance
  • lactonase
  • quorum sensing

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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