Active efflux influences the potency of quorum sensing inhibitors in Pseudomonas aeruginosa.
Many bacteria regulate gene expression through a cell-cell signaling process called quorum sensing (QS). In proteobacteria, QS is largely mediated by signaling molecules known as N-acylated L-homoserine lactones (AHLs) and their associated intracellular LuxR-type receptors. The design of non-native small molecules capable of inhibiting LuxR-type receptors (and thereby QS) in proteobacteria is an active area of research, and numerous lead compounds are AHL derivatives that mimic native AHL molecules. Much of this previous work has focused on the pathogen Pseudomonas aeruginosa, which controls an arsenal of virulence factors and biofilm formation through QS. The MexAB-OprM efflux pump has been shown to play a role in the secretion of the major AHL signal in P. aeruginosa, N-(3-oxododecanoyl) L-homoserine lactone. In the current study, we show that a variety of non-native AHLs and related derivatives capable of inhibiting LuxR-type receptors in P. aeruginosa display significantly higher potency in a P. aeruginosa Δ(mexAB-oprM) mutant, suggesting that MexAB-OprM also recognizes these compounds as substrates. We also demonstrate that the potency of 5,6-dimethyl-2-aminobenzimidazole, recently shown to be a QS and biofilm inhibitor in P. aeruginosa, is not affected by the presence/absence of the MexAB-OprM pump. These results have implications for the use of non-native AHLs and related derivatives as QS modulators in P. aeruginosa and other bacteria, and provide a potential design strategy for the development of new QS modulators that are resistant to active efflux.
Department of Chemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, WI 53706 (USA).
Joseph D
JD
Moore
Joseph P
JP
Gerdt
Nora R
NR
Eibergen
Helen E
HE
Blackwell
D054742:Acyl-Butyrolactones / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000378:metabolism; D018441:Biofilms / Q000187:drug effects; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D011485:Protein Binding; D011550:Pseudomonas aeruginosa / Q000502:physiology*; D053038:Quorum Sensing / Q000187:drug effects; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism
D054742:Acyl-Butyrolactones; D001425:Bacterial Outer Membrane Proteins; D026901:Membrane Transport Proteins; C118598:MexA protein, Pseudomonas aeruginosa; C118597:MexB protein, Pseudomonas aeruginosa; C402263:OprM protein, Pseudomonas aeruginosa; D012097:Repressor Proteins; D015534:Trans-Activators; C064778:LuxR autoinducer binding proteins
MexAB-OprM; antiproliferation; efflux pumps; homoserine lactones; inhibitors; quorum sensing