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primary topic: Preclinical evaluation of tridecaptin M: in vitro and in vivo efficacy against colistin-resistant Gram-negative bacterial pathogens and pharmacokinetics

Preclinical evaluation of tridecaptin M: in vitro and in vivo efficacy against colistin-resistant Gram-negative bacterial pathogens and pharmacokinetics
type: AcademicArticle
type: Article
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
volume: 69
issue: 10
author list: authors
type: EPrint
type: ArticleEPrint
is part of: repository

American Society for Microbiology
type: Organization

Antimicrob. Agents Chemother.
type: Collection

Rajneesh Dadwal
type: Person
given name: Rajneesh
family name: Dadwal

Parminder Kaur
type: Person
given name: Parminder
family name: Kaur

Vrushali Raka
type: Person
given name: Vrushali
family name: Raka

Shubhangi Kansal
type: Person
given name: Shubhangi
family name: Kansal

Archana Angrup
type: Person
given name: Archana
family name: Angrup

Hemraj Nandanwar
type: Person
given name: Hemraj
family name: Nandanwar

Manoj Jangra
type: Person
given name: Manoj
family name: Jangra

Pallab Ray
type: Person
given name: Pallab
family name: Ray

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primary topic: Preclinical evaluation of tridecaptin M: in vitro and in vivo efficacy against colistin-resistant Gram-negative bacterial pathogens and pharmacokinetics