Multidrug efflux in intrinsic resistance to trimethoprim and sulfamethoxazole in Pseudomonas aeruginosa

Abstract

Pseudomonas aeruginosa possesses at least two multiple drug efflux systems which are defined by the outer membrane proteins OprM and OprJ. We have found that mutants overexpressing OprM were two- and eightfold more resistant than their wild-type parent to sulfamethoxazole (SMX) and trimethoprim (TMP), respectively. For OprJ-overproducing strains, MICs of TMP increased fourfold but those of SMX were unchanged. Strains overexpressing OprM, but not those overexpressing OprJ, became hypersusceptible to TMP and SMX when oprM was inactivated. The wild-type antibiotic profile could be restored in an oprM mutant by transcomplementation with the cloned oprM gene. These results demonstrate that the mexABoprM multidrug efflux system is mainly responsible for the intrinsic resistance of P. aeruginosa to TMP and SMX.

Evidence of MexT-Independent Overexpression of MexEF-OprN Multidrug Efflux Pump of Pseudomonas aeruginosa in Presence of Metabolic Stress

“…It is known to cause a variety of infections including pneumonia, bloodstream infections, urinary tract infections, endocarditis, and burn wound infections [1], [2], [3], [4], [5], [6], [7]. Infections caused by P. aeruginosa pose a considerable challenge in the clinical settings owing to its high intrinsic resistance to almost all antibiotics in clinical use [8], [9], [10], [11], [12], [13], [14]. Energy-mediated efflux of antibiotics by Resistance-Nodulation-Cell Division (RND) pumps in P. aeruginosa is considered the major factor responsible for its high antibiotic resistance.…”

Novel phytochemical–antibiotic conjugates as multitarget inhibitors of Pseudomononas aeruginosa GyrB/ParE and DHFR

“…Sulfonamides act as structural analogs of p-aminobenzoic acid, competitively inhibiting the additional enzyme dihydropteroate synthase in the folate pathway, which catalyzes the addition of p-aminobenzoic acid to dihydropterin pyrophosphate to form pteroic acid 61. Due to the low outer membrane permeability, poor affinity, and characteristic intrinsic resistance by efflux pumps, the antibacterial potency of trimethoprim and sulfonamides are limited (with MICs usually in the resistance range) 62. Thus, the rational design and development of novel hybrid entities that can inhibit both GyrB/ParE and DHFR enzymes would be beneficial in treating various multidrug resistant phenotypes.…”

In vivo impact of the MexAB-OprM efflux system on β-lactam efficacy in an experimental model of Pseudomonas aeruginosa infection

“…PAO4098E and PAO4098ET, two isogenic mutants of PAO1 described previously [5,6], were obtained from Prof. P. Plésiat. The mutants PAO4098E and PAO4098ET were obtained from PAO4098 (FP-met-9020 pro-9024 bla P9208), which produces a low, non-inducible level of ␤-lactamase.…”