Harnessing metabolic dependence-driven antibiotic synergy to eradicate tolerant Pseudomonas aeruginosa

  • J Antimicrob Chemother. 2026 Jun 3;81(7):dkag204. doi: 10.1093/jac/dkag204.
Yuanye Ji  1 ,  Ping Tuo  1 ,  Chunyan Ruan  1 ,  Sijia Zhang  1 ,  Fajiu Wang  2 ,  Jia Shen  3 ,  Peng Zhu  1
Affiliations
  • 1. Centre for Medical Research, Ningbo No.2 Hospital, Ningbo City, Zhejiang Province, China.
  • 2. Department of Thoracic Surgery, Ningbo No.2 Hospital, Ningbo City, Zhejiang Province, China.
  • 3. Department of Hepatopancreatobiliary Surgery Dept.1, Ningbo No.2 Hospital, Ningbo City, Zhejiang Province, China.
PMID: 42267541 DOI: 10.1093/jac/dkag204
Abstract

Background: Pseudomonas aeruginosa is a major nosocomial pathogen, and its Antibiotic tolerance under low-metabolism conditions severely compromises clinical efficacy, presenting a significant therapeutic challenge.

Objectives: A quantitative assessment of the metabolic dependence of clinically relevant Antibiotics against P. aeruginosa was conducted, and a novel combination strategy capable of eradicating its low-metabolic populations was developed.

Methods: We established a gradient nutrient model (0%-100% LB) to simulate a continuum of metabolic states. Through linear regression analysis correlating ATP levels with bactericidal efficiency, we developed a Metabolic Dependence Index classification system. Leveraging this system, we designed a Strongly Metabolism-Dependent (SMD) + Weakly Metabolism-Dependent (WMD) synchronous combination strategy, which was subsequently validated using five clinical isolates.

Results: Low-metabolism populations exhibited significantly reduced susceptibility to SMD agents but unaltered tolerance to WMD Antibiotics. The SMD + WMD combination achieved enhanced killing of low-metabolism bacteria (>99.999% killing) with a marked dose reduction in vitro. This strategy also improved in vitro clearance efficacy compared to monotherapy. Collectively, our work provides a quantitative framework for targeting metabolic heterogeneity to overcome Antibiotic tolerance.

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