TXA11114: Discovery of an In Vivo Efficacious Efflux Pump Inhibitor (EPI) That Potentiates Levofloxacin Against Pseudomonas aeruginosa
Abstract
Objectives: Multidrug-resistant (MDR) Pseudomonas aeruginosa represents a major clinical challenge, driven in part by resistance-nodulation-division (RND) efflux pumps that reduce intracellular antibiotic concentrations and limit the efficacy of many antibacterial agents, including fluoroquinolones. The aim of this study was to identify and characterize TXA11114 as a small-molecule efflux pump inhibitor (EPI) capable of restoring the activity of the fluoroquinolone levofloxacin against MDR P. aeruginosa. Methods: The antibacterial activity of the TXA11114-levofloxacin combination was evaluated using minimum inhibitory concentration (MIC) assays against panels of clinical isolates. Mechanistic studies included levofloxacin accumulation assays, ethidium bromide accumulation assays, outer-membrane permeability measurements, and whole-genome sequencing of mutants with altered potentiation phenotypes. In vivo efficacy was evaluated in murine thigh and lung infection models, while preliminary safety and drug-like properties were assessed using cytotoxicity assays and in vitro ADME profiling. Results: The TXA11114-levofloxacin combination produced > 1 log10 CFU reductions in bacterial burden in murine thigh and lung infection models, exceeding the activity of levofloxacin monotherapy. TXA11114 markedly potentiated levofloxacin activity, producing substantial reductions in levofloxacin MIC values across multiple MDR clinical isolates, and also enhanced the activity of several…
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