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| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Artículo científico |
| Language: | en |
| Published: |
ACS infectious diseases
2025
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| Subjects: | |
| Online Access: | https://pubmed.ncbi.nlm.nih.gov/41116744/ |
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Table of Contents:
- Glutamine Potentiates Cefoperazone-Sulbactam Activity against by Increasing Drug Uptake and ROS. Wang, Shi-Wen Shi, Zheng-Qi Zhu, Jia-Xin Xiang, Jiao Chen, Yue-Tao Li, Shao-Hua Zhao, Xian-Liang Zeng, Ying-Yue Tao, Yuan Fu, Huan-Zhe Lin, Hui-Yin Tang, Jin Huang, Xiao-Xia Wang, Xin Peng, Xuan-Xian Wu, Kui-Hai Zhang, Tian-Tuo Li, Hui Acinetobacter baumannii Cefoperazone Sulbactam Glutamine Animals Reactive Oxygen Species Anti-Bacterial Agents Mice Acinetobacter Infections Drug Synergism Microbial Sensitivity Tests Humans Drug Resistance, Multiple, Bacterial Female The combination of an antibiotic with a metabolic reprogramming agent is anticipated to emerge as a promising therapeutic strategy against antibiotic-resistant bacteria, although this hypothesis requires validation through preclinical pharmacodynamic studies. This study evaluated the preclinical pharmacodynamic profile of cefoperazone-sulbactam (SCF) combined with glutamine against 237 clinical isolates, including 26 antibiotic-sensitive (S-AB), 8 multidrug-resistant (MDR-AB), and 203 carbapenem-resistant strains (CR-AB). The combination demonstrated synergistic efficacy in 224 cases (94.51%), equivalence in 10 (4.22%), and no interaction in 3 (1.27%) compared with SCF monotherapy. Time-kill assays, bacterial load quantification, and murine infection models consistently validated these findings, with therapeutic effects remaining stable despite variations in calcium concentrations and pH gradients. Glutamine slows the development of SCF resistance, prolongs the postantibiotic effect, and reduces mutation frequency. Mechanistically, glutamine reprograms bacterial metabolism from an antibiotic-resistant state to an antibiotic-sensitive state, thereby enhancing reactive oxygen species (ROS) production, which combines with increased drug uptake to potentiate SCF killing. This accelerated drug influx surpasses the clearance capacity mediated by efflux pumps and enzymatic degradation, resulting in increased bacterial eradication through synergy with ROS. These findings suggest that the synergistic combination holds the potential for developing therapeutic candidates against MDR-AB and CR-AB.