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<p>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<sub>50</sub>: 0.0078–0.0156 mg/L; 64–128-fold lower than vancomycin/linezolid) and bactericidal activity (MBC<sub>50</sub> = 4–16 × MIC). Murine systemic and localized infection models showed superior efficacy (ED<sub>50</sub>: 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<sub>0–24</sub>/MIC and %T &gt; MIC as primary efficacy drivers (R<sup>2</sup> ≥ 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 (&lt;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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月1日

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  • Xisheng Xiong,
  • Junjian Qian,
  • Lang Wang,
  • Jiawei Liu,
  • Lulu Zhang,
  • Kai Diao,
  • Tao Tang,
  • Xianliang Zhang,
  • Xuri Wu,
  • Yijun Chen

摘要

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 AUC0–24/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.