creators_name: Raka, Vrushali creators_name: Jangra, Manoj creators_name: Kaur, Parminder creators_name: Dadwal, Rajneesh creators_name: Kansal, Shubhangi creators_name: Angrup, Archana creators_name: Ray, Pallab creators_name: Nandanwar, Hemraj type: article datestamp: 2026-02-01 13:54:29 lastmod: 2026-02-01 13:54:29 metadata_visibility: show title: Preclinical evaluation of tridecaptin M: in vitro and in vivo efficacy against colistin-resistant Gram-negative bacterial pathogens and pharmacokinetics keywords: AMPs; colistin-resistant Klebsiella pneumoniae; gram-negative bacteria; multidrug-resistant; pharmacokinetics; preclinical; tridecaptins abstract: The escalating threat of antimicrobial resistance (AMR), particularly among gram-negative pathogens, necessitates the development of novel therapeutic agents. Tridecaptins, a class of non-ribosomally synthesized lipopeptides with a novel mode of action, have garnered renewed interest in the fight against AMR. Our group previously identified tridecaptin M, a compound with a promising safety profile, prompting further investigation into its efficacy and preclinical characteristics. Here, we show that tridecaptin M exhibits potent activity against multidrug-resistant (MDR) Klebsiella pneumoniae and Escherichia coli without cross-resistance to colistin. It effectively inhibits biofilm formation and disrupts 50% of established biofilm at 10 µg/mL. Tridecaptin M demonstrates a favorable safety profile, as it does not inhibit the cardiac hERG channel and shows minimal interaction with cytochrome P450 enzymes, with no ICâ� â�� detected up to 44.6 µg/mL. In vivo toxicity studies via subcutaneous administration confirm its safety up to 600 mg/kg, whereas intravenous administration reveals acute toxicity at \geq30 mg/kg, with biochemical evidence of skeletal muscle, cardiac, and hepatic involvement. In mouse infection models using a colistin-resistant MDR strain of K. pneumoniae reveal the in vivo potential of tridecaptin M and a dose-dependent efficacy at 10 mg/kg, 20 mg/kg, 50 mg/kg, and 100 mg/kg doses, showing a non-linear relationship. Tridecaptin M is metabolized by liver microsomes, with low clearance, and pharmacokinetic analysis in rats indicates favorable attributes, with a terminal half-life (Tâ��/â��) of 3.65 h intravenously and 8.81 h subcutaneously. Collectively, these data support the continued preclinical development of tridecaptin M as a promising candidate for treating severe gram-negative infections. date: 2025-10 publication: Antimicrob. Agents Chemother. volume: 69 number: 10 publisher: American Society for Microbiology pagerange: e0108325 citation: Raka, Vrushali and Jangra, Manoj and Kaur, Parminder and Dadwal, Rajneesh and Kansal, Shubhangi and Angrup, Archana and Ray, Pallab and Nandanwar, Hemraj (2025) Preclinical evaluation of tridecaptin M: in vitro and in vivo efficacy against colistin-resistant Gram-negative bacterial pathogens and pharmacokinetics. Antimicrob. Agents Chemother., 69 (10). e0108325.