Target (MexB)- and Efflux-Based Mechanisms Decreasing the Effectiveness of the Efflux Pump Inhibitor D13-9001 in Pseudomonas aeruginosa PAO1: Uncovering a New Role for MexMN-OprM in Efflux of β-Lactams and a Novel Regulatory Circuit (MmnRS) Controlling MexMN Expression

Efflux pumps contribute to antibiotic resistance in Gram-negative pathogens. Correspondingly, efflux pump inhibitors (EPIs) may reverse this resistance. D13-9001 specifically inhibits MexAB-OprM in Mutants with decreased susceptibility to MexAB-OprM inhibition by D13-9001 were identified, and these...

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Published in:	Antimicrobial agents and chemotherapy Vol. 63; no. 2
Main Authors:	Ranjitkar, Srijan, Jones, Adriana K, Mostafavi, Mina, Zwirko, Zachary, Iartchouk, Oleg, Barnes, S Whitney, Walker, John R, Willis, Thomas W, Lee, Patrick S, Dean, Charles R
Format:	Journal Article
Language:	English
Published:	United States American Society for Microbiology 01-02-2019
Subjects:	beta-Lactams beta-Lactams - pharmacology Imipenem - pharmacology Mechanisms of Resistance Microbial Sensitivity Tests Monobactams - pharmacology Piperidines Piperidines - pharmacology Pseudomonas aeruginosa Pseudomonas aeruginosa - drug effects Pseudomonas aeruginosa - genetics Quaternary Ammonium Compounds Quaternary Ammonium Compounds - pharmacology Tazobactam - pharmacology Thienamycins - pharmacology Transcriptome - genetics β-lactams Pseudomonas aeruginosa efflux pump inhibitor drug resistance mechanisms heavy metals efflux pumps
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Summary:	Efflux pumps contribute to antibiotic resistance in Gram-negative pathogens. Correspondingly, efflux pump inhibitors (EPIs) may reverse this resistance. D13-9001 specifically inhibits MexAB-OprM in Mutants with decreased susceptibility to MexAB-OprM inhibition by D13-9001 were identified, and these fell into two categories: those with alterations in the target MexB (F628L and ΔV177) and those with an alteration in a putative sensor kinase of unknown function, PA1438 (L172P). The alterations in MexB were consistent with reported structural studies of the D13-9001 interaction with MexB. The PA1438 alteration mediated a >150-fold upregulation of MexMN pump gene expression and a >50-fold upregulation of PA1438 and the neighboring response regulator gene, PA1437. We propose that these be renamed and for ex egulator and ex sensor, respectively. MexMN was shown to partner with the outer membrane channel protein OprM and to pump several β-lactams, monobactams, and tazobactam. Upregulated MexMN functionally replaced MexAB-OprM to efflux these compounds but was insusceptible to inhibition by D13-9001. MmnS also mediated a decrease in susceptibility to imipenem and biapenem that was independent of MexMN-OprM. Expression of , encoding the uptake channel for these compounds, was downregulated, suggesting that this channel is also part of the MmnSR regulon. Transcriptome sequencing (RNA-seq) of cells encoding MmnS revealed, among other things, an interrelationship between the regulation of and genes involved in heavy metal resistance.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 S.R. and A.K.J. contributed equally to this article. Citation Ranjitkar S, Jones AK, Mostafavi M, Zwirko Z, Iartchouk O, Barnes SW, Walker JR, Willis TW, Lee PS, Dean CR. 2019. Target (MexB)- and efflux-based mechanisms decreasing the effectiveness of the efflux pump inhibitor D13-9001 in Pseudomonas aeruginosa PAO1: uncovering a new role for MexMN-OprM in efflux of β-lactams and a novel regulatory circuit (MmnRS) controlling MexMN expression. Antimicrob Agents Chemother 63:e01718-18. https://doi.org/10.1128/AAC.01718-18. Present address: Srijan Ranjitkar, Epizyme, Cambridge, Massachusetts, USA.
ISSN:	0066-4804 1098-6596
DOI:	10.1128/AAC.01718-18