title: Interactions among quorum sensing inhibitors.
abstract: Many pathogenic bacteria use quorum sensing (QS) systems to regulate the expression of virulence genes in a density-dependent manner. In one widespread QS paradigm the enzyme LuxI generates a small diffusible molecule of the acyl-homoserine lactone (AHL) family; high cell densities lead to high AHL levels; AHL binds the transcription factor LuxR, triggering it to activate gene expression at a virulence promoter. The emergence of antibiotic resistance has generated interest in alternative anti-microbial therapies that target QS. Inhibitors of LuxI and LuxR have been developed and tested in vivo, and can act at various levels: inhibiting the synthesis of AHL by LuxI, competitively or non-competitively inhibiting LuxR, or increasing the turnover of LuxI, LuxR, or AHL. Here use an experimentally validated computational model of LuxI/LuxR QS to study the effects of using inhibitors individually and in combination. The model includes the effect of transcriptional feedback, which generates highly non-linear responses as inhibitor levels are increased. For the ubiquitous LuxI-feedback virulence systems, inhibitors of LuxI are more effective than those of LuxR when used individually. Paradoxically, we find that LuxR competitive inhibitors, either individually or in combination with other inhibitors, can sometimes increase virulence by weakly activating LuxR. For both LuxI-feedback and LuxR-feedback systems, a combination of LuxR non-competitive inhibitors and LuxI inhibitors act multiplicatively over a broad parameter range. In our analysis, this final strategy emerges as the only robust therapeutic option.
authors.affiliation: National Centre for Biological Sciences, Tata Institute of Fundamental Research, UAS/GKVK Campus, Bangalore, India.
authors.forename: Rajat
authors.initials: R
authors.lastname: Anand
authors.forename: Navneet
authors.initials: N
authors.lastname: Rai
authors.forename: Mukund
authors.initials: M
authors.lastname: Thattai
mesh_terms: D054742:Acyl-Butyrolactones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000465:Algorithms; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008954:Models, Biological; D053038:Quorum Sensing / Q000187:drug effects* / Q000502:physiology*; D012097:Repressor Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D015534:Trans-Activators / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D054742:Acyl-Butyrolactones; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; C085427:LuxI protein, Bacteria; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C064778:LuxR autoinducer binding proteins