The Art of War with Pseudomonas aeruginosa: Targeting Mex Efflux Pumps Directly to Strategically Enhance Antipseudomonal Drug Efficacy

Abstract

Pseudomonas aeruginosa (P. aeruginosa) poses a grave clinical challenge due to its multidrug resistance (MDR) phenotype, leading to severe and life-threatening infections. This bacterium exhibits both intrinsic resistance to various antipseudomonal agents and acquired resistance against nearly all available antibiotics, contributing to its MDR phenotype. Multiple mechanisms, including enzyme production, loss of outer membrane proteins, target mutations, and multidrug efflux systems, contribute to its antimicrobial resistance. The clinical importance of addressing MDR in P. aeruginosa is paramount, and one pivotal determinant is the resistance-nodulation-division (RND) family of drug/proton antiporters, notably the Mex efflux pumps. These pumps function as crucial defenders, reinforcing the emergence of extensively drug-resistant (XDR) and pandrug-resistant (PDR) strains, which underscores the urgency of the situation. Overcoming this challenge necessitates the exploration and development of potent efflux pump inhibitors (EPIs) to restore the efficacy of existing antipseudomonal drugs. By effectively countering or bypassing efflux activities, EPIs hold tremendous potential for restoring the antibacterial activity against P. aeruginosa and other Gram-negative pathogens. This review focuses on concurrent MDR, highlighting the clinical significance of efflux pumps, particularly the Mex efflux pumps, in driving MDR. It explores promising EPIs and delves into the structural characteristics of the MexB subunit and its substrate binding sites.

Evaluation of fortimicin antibiotic combinations against MDR Pseudomonas aeruginosa and resistome analysis of a whole genome sequenced pan-drug resistant isolate

“…Within our isolate, resistance-nodulation-division (RND) efflux pump that differs with its substrate specificities and encoded by diverse gene determinants as MexAB-OprM and MexCD-OprJ were the most represented. This findings echoes with Avakh et al, who highlighted role of Mex pumps in strengthening the emergence of XDR and PDR strains [ 36 ]. Additionally, ParR/ParS that confers resistance to all the tested antibiotic classes through regulation of RND- efflux pump and outer membrane porins [ 37 ], were also detected.…”

“…The extracted genomic DNA was sequenced using the next generation sequencing and construction of the library was performed using the Nextera XT DNA Library preparation kit (San Diego, CA 92,122 USA) https://www.illumina.com/products/by-type/sequencing-kits/library-prep-kits/nextera-xt-dna.html ( accessed on 23 October 2023). The sequence contigs were uploaded into the BV-BRC [ 36 ] website ( https://www.bv-brc.org/ ) (accessed on 03 December 2023) and annotated [ 37 ]. The final assembled contigs as FASTA format was submitted to the NCBI Sequence Read Archive (SRA) database under the BioProject accession code PRJNA1023276 ( https://www.ncbi.nlm.nih.gov/sra/PRJNA1023276 ).…”

Targeting FMN, TPP, SAM-I, and glmS Riboswitches with Chimeric Antisense Oligonucleotides for Completely Rational Antibacterial Drug Development

“…These bacteria are separated into three categories: critical priority, high priority, and medium priority pathogens for research and development of new antibiotics. Acinetobacter baumannii, Enterobacteriaceae, and Pseudomonas aeruginosa are carbapenemresistant in the first group [4,46,47]. For example, FMN, glmS, cobalamin, lysine, and other riboswitches are found in Acinetobacter baumanii's genome.…”

Rapid detection of mexX in Pseudomonas aeruginosa based on CRISPR-Cas13a coupled with recombinase polymerase amplification

“…Because of their significance in the drug tolerance mechanism, efflux pumps have emerged as a crucial therapeutic target. Antibiotic resistance can be combated by preventing these efflux pumps from working ( Avakh et al, 2023 ). However, the modern quick and effective detection methods for efflux pump genes are scarce, limiting the prompt detection and treatment of resistant P. aeruginosa .…”