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

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 (MIC₅₀: 0.0078-0.0156 mg/L; 64-128-fold lower than vancomycin/linezolid) and bactericidal activity (MBC₅₀ = 4-16 × MIC). Murine systemic and localized infection models showed superior efficacy (ED₅₀: 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 (R² ≥ 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.