@article{open3261,
          volume = {69},
          number = {10},
           month = {October},
          author = {Vrushali Raka and Manoj Jangra and Parminder Kaur and Rajneesh Dadwal and Shubhangi Kansal and Archana Angrup and Pallab Ray and Hemraj Nandanwar},
           title = {Preclinical evaluation of tridecaptin M: in vitro and in vivo efficacy against colistin-resistant Gram-negative bacterial pathogens and pharmacokinetics},
       publisher = {American Society for Microbiology},
            year = {2025},
         journal = {Antimicrob. Agents Chemother.},
           pages = {e0108325},
        keywords = {AMPs; colistin-resistant Klebsiella pneumoniae; gram-negative bacteria; multidrug-resistant; pharmacokinetics; preclinical; tridecaptins},
             url = {http://crdd.osdd.net/open/3261/},
        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 {\^A}?g/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 IC{\^a}? {\^a}?? detected up to 44.6 {\^A}?g/mL. In vivo toxicity studies via subcutaneous administration confirm its safety up to 600 mg/kg, whereas intravenous administration reveals acute toxicity at {$\backslash$}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 (T{\^a}??/{\^a}??) 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.}
}