DUAL APPROACH TO REDUCE TOXICITY IN POLYMYXINS AND REGAIN ACTIVITY AGAINST COLISTIN-RESISTANT STRAINS

Antibacterial resistance is rising globally, with particular concern involving multidrug-resistant Gram-negative pathogens listed in the WHO Global Priority List (2024), i. e. carbapenem-resistant and third-generation cephalosporin-resistant Escherichia coli and Klebsiella pneumoniae and also carbapenem-resistant Pseudomonas aeruginosa. In this study, we present a dual strategy to reduce polymyxin B and colistin toxicity while maintaining efficacy in the murine model of infection. We used a disulfide-based chemical modification (soft-drug approach) alongside a combination therapy with a clinically approved compound. We will present in vitro microbiological testing (MIC against MDR gram negative bacteria including colistin-resistant strains such as K. pneumoniae ST147), in vivo pharmacokinetic data, acute toxicity and safety evaluation (nephrotoxicity and biomarkers KIM-1, clusterin, NGAL, THF-α) and efficacy in clinically relevant murine infection sepsis models. Taken together, the combination approach increased the tolerated dose of polymyxins by up to fivefold in mice, from 20 to 100 mg/kg subcutaneously and from 4 to 20 mg/kg intravenously, while maintaining antibacterial efficacy.

(https://jpiamr.eu/projects/muryxin/)