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Antimicrob Agents Chemother. 2018 Nov 12. pii: AAC.01718-18. doi: 10.1128/AAC.01718-18. [Epub ahead of print]

Target (MexB) and efflux based mechanisms decreasing the effectiveness of the efflux pump inhibitor D13-9001 in P. aeruginosa PAO1: uncovering a new role for MexMN-OprM in efflux of β-lactams and a novel regulatory circuit (MmnRS) controlling MexMN expression.

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Infectious Diseases, Novartis Institutes for Biomedical Research, Emeryville CA.
Biotherapeutic and Analytical Technologies, Novartis Institutes for Biomedical Research, Cambridge MA.
Genomics Institute of Novartis Research Foundation (GNF), San Diego CA.
Infectious Diseases, Novartis Institutes for Biomedical Research, Emeryville CA


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 P. aeruginosa Mutants with decreased susceptibility to MexAB-OprM inhibition by D13-9001 were identified and these fell into two categories; those having alterations in the target MexB (F628L and ΔV177) and those with mutations in PA1438 (L172P substitution) which encoded a putative sensor kinase of unknown function. The alterations in MexB were consistent with reported structural studies of D13-9001 interaction with MexB. The PA1438L172P alteration mediated a >150-fold upregulation of MexMN pump gene expression and >50-fold upregulation of PA1438 and the neighboring response regulator gene PA1437. We propose that these be renamed as mmnR/mmnS for MexMN Regulator and Sensor. 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. MmnSL172P also mediated a decrease in susceptibility to imipenem / biapenem that was independent of MexMN-OprM. Expression of oprD, encoding the uptake channel for these compounds was downregulated, suggesting that this channel is also part of the MmnSR regulon. RNA-seq of cells encoding MmnSL172P revealed among other things an interrelationships between regulation of mexMN and genes involved in heavy metal resistance.


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