Xiang Jiao, Wang Xin, Lin Huiyin, Yang Lifen, Huang Xiaoxia, Chen Yuetao, Zeng Yingyue, Li Shaohua, Zhao Xianliang, Wang Shiwen, Tao Yuan, Fu Huanzhe, Shi Zhengqi, Wu Kuihai, Peng Xuanxian, Li Hui, Tang Jin, Chen Zhuanggui
State Key Laboratory of Bio-Control, Third Affiliated Hospital, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
Hanzhong Central Hospital, Hanzhong, China.
Front Microbiol. 2025 Jul 3;16:1631646. doi: 10.3389/fmicb.2025.1631646. eCollection 2025.
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.
This study evaluated the preclinical pharmacodynamic profile of cefoperazone-sulbactam (SCF) combined with glutamine against 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.
These findings suggest that the synergistic combination holds potential for developing therapeutic candidates against MDR-PA and CR-PA.
抗生素与代谢重编程剂联合使用有望成为一种有前景的抗耐药菌治疗策略，不过这一假设需要通过临床前药效学研究来验证。
本研究评估了头孢哌酮-舒巴坦（SCF）联合谷氨酰胺针对临床分离株的临床前药效学特征，这些分离株包括54株抗生素敏感菌（S-PA）、20株多重耐药菌（MDR-PA）和185株碳青霉烯耐药菌（CR-PA）。
与SCF单药治疗相比，联合用药在251例（96.9%）中显示出协同疗效，7例（2.7%）中显示出等效性，1例（0.4%）中无相互作用。时间杀菌试验、细菌载量定量和小鼠感染模型一致验证了这些结果，治疗效果在钙浓度和pH梯度下保持稳定。谷氨酰胺减缓了SCF耐药性的发展，延迟了抗生素后效应，并降低了突变频率。从机制上讲，谷氨酰胺将细菌代谢从耐药状态重编程为敏感状态，从而增强膜通透性并增加药物摄取。这种加速的药物流入超过了由外排泵和酶降解介导的清除能力，导致细菌清除增加。
这些发现表明，这种协同联合用药在开发针对MDR-PA和CR-PA的治疗候选药物方面具有潜力。
