News|Videos|June 23, 2026
Efflux Pump Inhibitor Restores Azithromycin Activity Against Multidrug-Resistant Gram-Negative Pathogens
Preclinical findings demonstrate that the novel efflux pump inhibitor TXA14007 significantly enhances azithromycin activity against multidrug-resistant Gram-negative bacteria, supporting a potential new oral treatment strategy for difficult-to-treat infections. Jesus Rosado-Lugo, PhD, offers insights on the study at ASM Microbe 2026.
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Multidrug-resistant (MDR) Gram-negative pathogens such as Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii continue to pose a significant threat to public health, with few effective oral treatment options available. New preclinical data suggest that TXA14007, a novel efflux pump inhibitor (EPI), developed by TAXIS Pharmaceuticals, may help overcome one of the key resistance mechanisms limiting the utility of azithromycin against these organisms.
"Gram-negative bacteria have these pumps that allow them to expel antibiotics out of the cell, and if the antibiotic is out of the cell, it doesn't work anymore," Jesus Rosado-Lugo, PhD, director of Microbiology at TAXIS Pharmaceuticals, said.
TXA14007 is a dihydrobenzo-azepinoindolone compound designed to block bacterial efflux pumps that actively remove antibiotics from the cell. In laboratory testing, the agent reduced azithromycin minimum inhibitory concentrations by 8- to 32-fold across reference strains and carbapenem-resistant clinical isolates of E coli, K pneumoniae, and A baumannii, including strains carrying macrolide resistance determinants.
Mechanistic studies showed that TXA14007 inhibited efflux activity in a concentration-dependent manner, resulting in increased intracellular accumulation of azithromycin. The combination converted azithromycin’s activity from bacteriostatic to bactericidal and significantly reduced the emergence of resistance in time-kill and frequency-of-resistance assays.
"We're very happy to see that the TXA-14007 and azithromycin combination not only increases the activity of azithromycin, but it lowers or in some cases eliminates the emergence of resistance," said Rosado-Lugo, who presented findings on the company’s investigational therapy at the recent ASM Microbe.
Structural analyses further supported the mechanism of action. High-resolution X-ray crystallography revealed that TXA14007 binds directly within the deep substrate-binding pocket of the AcrB efflux transporter, providing molecular confirmation of efflux inhibition.
The combination also demonstrated efficacy in vivo. In a murine thigh infection model of E coli, TXA14007 enhanced azithromycin activity and produced a greater than 1-log10 reduction in bacterial burden compared with azithromycin alone, with effects increasing in a dose-dependent manner.
In addition to its antimicrobial potentiation, TXA14007 exhibited favorable drug-like properties, including high aqueous solubility, pharmacokinetics complementary to azithromycin, and a favorable safety profile. Investigators reported minimal cytotoxicity, hemolysis, nephrotoxicity, and off-target activity.
The findings support efflux pump inhibition as a promising strategy to repurpose existing antibiotics for MDR Gram-negative infections and position TXA14007 as a potential first-in-class adjunctive therapy aimed at restoring the effectiveness of azithromycin against resistant pathogens.
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