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

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 IC₅₀ 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 ≥30  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 (T₁/₂) 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.