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Pharmacokinetic and pharmacodynamic studies of injectable nocathiacin as a novel antibacterial agent

Year: 2025

Type: article

Abstract: The extreme hydrophobicity of nocathiacin, a potent thiopeptide antibiotic against multidrug-resistant (MDR) Gram-positive pathogens, has limited its clinical development. This study formulated an injectable lyophilized nocathiacin with enhanced solubility (12.59 mg/mL). In vitro testing against 1050 clinical isolates demonstrated exceptional potency (MIC 50 : 0.0078–0.0156 mg/L; 64–128-fold lower than vancomycin/linezolid) and bactericidal activity (MBC 50 = 4–16 × MIC). Murine systemic and localized infection models showed superior efficacy (ED 50 : 0.64–1.96 mg/kg; ~3 log (CFU/g) reduction in lung/thigh at 2/8 mg/kg). PK/PD analysis in immunocompromised mice identified AUC 0–24 /MIC and %T > MIC as primary efficacy drivers (R 2 ≥ 0.97), indicating time-dependent killing. Favorable PK in rats/monkeys included moderate half-lives (4.7–5.5 h), biliary-dominated excretion (26.01% parent drug), minimal renal clearance (<0.10%), and no CYP inhibition/induction or significant transporter interactions. These results support injectable nocathiacin as a promising clinical candidate for MDR Gram-positive infections.

Source: npj Antimicrobials and Resistance

DOI: 10.1038/s44259-025-00148-6