Lead optimization of a novel cyclic aryl-indole efflux pump inhibitor (EPI) series in combination with levofloxacin against Pseudomonas aeruginosa - Treatment of hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) caused by multidrug-resistant (MDR) P. aeruginosa infection remains a challenge at the clinic due to suboptimal responses to existing antibiotics. Around 42% of the 64,000 HAP cases with P. aeruginosa infection lead to death in the US annually. MDR P. aeruginosa is often associated with overexpression of multiple efflux pumps that limit the exposure of several classes of antibiotics rendering them ineffective. As a counterstrategy, TAXIS Pharmaceuticals is committed to finding effective anti-pseudomonal therapy involving novel efflux pump inhibitors (EPIs) as adjunctive with levofloxacin, to enhance its exposure in Gram-negative pathogens by blocking their efflux capabilities. During the hit-to-lead campaign of this program, our structure-activity relationship (SAR) efforts have successfully identified a 7-membered dihydrobenzo azepinoindolone compound (TXA14007) as the lead EPI with favorable ADME and physiochemical properties. TXA14007 shows remarkable potentiation of levofloxacin against MDR strains from CDC and WRAIR-MRSN collections as well as other MDR clinical isolates of P. aeruginosa retrieved from 63 countries and 3 US hospitals. Mechanistic studies indicate that TXA14007 specifically inhibits efflux pump activities, without affecting bacterial membrane integrity. Previous clinical development of EPIs has stalled or stopped due to either toxicity concerns or limited evidence for in vivo efficacy. In contrast, TAXIS’ TXA14007 has demonstrated durable, validated in vivo efficacy in murine lung infection model with wild-type P. aeruginosa in combination with levofloxacin. Moreover, TXA14007 has so far circumvented the major toxicological issues that plagued previous developmental EPIs, showing a relatively safer toxicology profile when screened for cytotoxicity, hemolytic activity, off-target receptor binding, hERG channel inhibition, in vitro nephrotoxicity, and acute toxicity. Further, a close analog of TXA14007 displays a complementary pharmacokinetic profile with levofloxacin in plasma and BALF samples of infected mice, thus ensuring maximum pharmacodynamic benefits. The goal of this SBIR phase II application is to optimize TXA14007 with a multiparametric SAR study to further improve its efficacy in terms of combination synergy and PK parameters, as well as further advancing our investigation into its (and analogs’) in vivo nephrotoxicity and cardiotoxicity profile. If successful, our phase II efforts will lead up to a preclinical candidate with a real chance to reach the clinic and save lives.
