ORIGINAL RESEARCH article
Front. Microbiol.
Sec. Antimicrobials, Resistance and Chemotherapy
Volume 16 - 2025 | doi: 10.3389/fmicb.2025.1631646
This article is part of the Research TopicBacterial Metabolites: Redefining Strategies to Combat Antimicrobial ResistanceView all articles
Glutamine Potentiates Cefoperazone-Sulbactam Activity against Pseudomonas aeruginosa by Increasing Membrane Permeability and Cellular Uptake
Provisionally accepted
Jiao Xiang1
Li-fen Yang2
Huiying Lin1
Yuetao Chen1Yingyue Zen1
Li Shaohua1
Xianliang Zhao3
Wang Shiwen1Yuan Tao1Huangzhe Fu1Jin Tang4Xiaoxia Huang4Xin Wang4Zhengqi Shi5Kuihai Wu5
Xuanxian Peng1
Hui Li1Zhuanggui Chen2*- 1Sun Yat-sen University, Guangzhou, China
- 2Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
- 3Shantou University, Shantou, Guangdong Province, China
- 4Hanzhong Central Hospital, Hanzhong, Shaanxi Province, China
- 5First People's Hospital of Foshan, Foshan, Guangdong Province, China
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The combination of an antibiotic with a metabolic reprogramming agent is anticipated to emerge as a promising therapeutic strategy against antibiotic-resistant bacteria, though this hypothesis requires validation through preclinical pharmacodynamic studies.Methods: This study evaluated the preclinical pharmacodynamic profile of cefoperazone-sulbactam (SCF) combined with glutamine against Pseudomonas aeruginosa clinical isolates, including 54 antibiotic-sensitive (S-PA), 20 multidrug-resistant (MDR-PA), and 185 carbapenem-resistant strains (CR-PA).The combination demonstrated synergistic efficacy in 251 cases (96.9%), equivalence in 7 (2.7%), and no interaction in 1 (0.4%) compared to SCF monotherapy. Time-kill assays, bacterial load quantification, and murine infection models consistently validated these findings, with therapeutic effects remaining stable by calcium concentrations and pH gradients. Glutamine slows the development of SCF resistance, delays the post-antibiotic effect, and reduces mutation frequency.Mechanistically, glutamine reprograms bacterial metabolism from an antibiotic-resistant to an antibiotic-sensitive state, thereby enhancing membrane permeability and increasing drug uptake. This accelerated drug influx surpasses the clearance capacity mediated by efflux pumps and enzymatic degradation, resulting in increased bacterial eradication.Conclusions: These findings suggest that the synergistic combination holds potential for developing therapeutic candidates against MDR-PA and CR-PA.
Keywords: Preclinical pharmacodynamics, Cefoperazone/sulbactam, multidrug resistance, Carbapenem resistance, Glutamine, Pseudomonas aeruginosa
Received: 20 May 2025; Accepted: 19 Jun 2025.
Copyright: © 2025 Xiang, Yang, Lin, Chen, Zen, Shaohua, Zhao, Shiwen, Tao, Fu, Tang, Huang, Wang, Shi, Wu, Peng, Li and Chen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Zhuanggui Chen, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510000, Guangdong Province, China
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