A MexR Mutation Which Confers Aztreonam Resistance to Pseudomonas aeruginosa

Abstract

Therapy for Pseudomonas aeruginosa infections is hard due to its high natural and acquirable antibiotic resistance. After colonization in the hosts, P. aeruginosa commonly accumulates genomic mutations which confer them antibiotic resistance and better adaptations to the host environment. Deciphering the mechanisms of antibiotic resistance development in the clinical setting may provide critical insights into the design of effective combinatory antibiotic therapies to treat P. aeruginosa infections. In this work, we demonstrate a resistance mechanism to aztreonam of a clinical isolate (ARP36) in comparison with a sensitive one (CSP18). RNAseq and genomic DNA resequencing were carried out to compare the global transcriptional profiles and in the clinical setting genomic profiles between these two isolates. The results demonstrated that hyperexpression of an efflux pump MexAB-OprM caused by a R70Q substitution in MexR, contributed to the increased resistance to aztreonam in the isolate ARP36. Simulation of mexR of ARP36 by gene editing in CSP18 conferred CSP18 an ARP36-like susceptibility to the aztreonam. The R70Q substitution prevented MexR from binding to the intergenic region between mexR and mexAB-oprM operon, with no impact on its dimerization. The presented experimental results explain for the first time why the clinically relevant R70Q substitution in the MexR derepresses the expression of mexAB-oprM in P. aeruginosa.

Comparative Metagenomic Study of Rhizospheric and Bulk Mercury-Contaminated Soils in the Mining District of Almadén

“…The MexAB-OprM and MexEF-OprN complexes are a protein assembly of membrane transporters that provide multi-resistance to antibiotics, identified primarily in Pseudomonas sp. and are highly linked to multi-resistance in P. aeruginosa ( Ma et al, 2021 ). As shown in Table 1 , there is high probability that these genes that could confer multi-resistance can be associated with the Pseudomonas identified in this manuscript.…”

Role of Efflux Pumps on Antimicrobial Resistance in Pseudomonas aeruginosa

“…The use of antibiotics selects P. aeruginosa strains with increased MexAB-OprM expression [ 137 , 138 ]. Several mutations in repressor genes have been associated with this phenomenon [ 139 ], in particular mutations causing translational disruption, such as nonsense substitutions and frameshifts [ 138 , 140 ], disruption by insertion sequences [ 139 , 141 ], and non-synonymous substitutions that alter the molecular structure of the repressors [ 137 , 142 ]. However, there are commonly reported non-synonymous substitutions, such as V126E in mexR , which are not associated with an increase in efflux pump expression [ 143 , 144 ].…”

Targeting the Holy Triangle of Quorum Sensing, Biofilm Formation, and Antibiotic Resistance in Pathogenic Bacteria

“…The mexCD-oprJ operon is repressed by NfxB [232]; and the mexEF-oprN operon is repressed by NfxC, while activated by the MexT transcriptional activator [233]. Mutation in MexR or NalC results in upregulation of mexAB-oprM, and resistance to aztreonam [234][235][236].…”

“…The mexCDeron is repressed by NfxB [232]; and the mexEF-oprN operon is repressed by NfxC activated by the MexT transcriptional activator [233]. Mutation in MexR or NalC in upregulation of mexAB-oprM, and resistance to aztreonam [234][235][236]. The efflux pump MexHI-OpmD exports the toxic metabolite anthranilate tha as a precursor of the autoinducer PQS [237].…”