Glutamine Potentiates Cefoperazone-Sulbactam Activity against Acinetobacter baumannii by Increasing Drug Uptake and ROS.

IF 3.8 2区 医学 Q2 CHEMISTRY, MEDICINAL
Shi-Wen Wang, Zheng-Qi Shi, Jia-Xin Zhu, Jiao Xiang, Yue-Tao Chen, Shao-Hua Li, Xian-Liang Zhao, Ying-Yue Zeng, Yuan Tao, Huan-Zhe Fu, Hui-Yin Lin, Jin Tang, Xiao-Xia Huang, Xin Wang, Xuan-Xian Peng, Kui-Hai Wu, Tian-Tuo Zhang, Hui Li
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Abstract

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 Acinetobacter baumannii 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.

谷氨酰胺通过增加药物摄取和ROS增强头孢哌酮舒巴坦抗鲍曼不动杆菌的活性。
抗生素与代谢重编程剂的组合有望成为对抗抗生素耐药细菌的一种有前途的治疗策略,尽管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)联合谷氨酰胺对237株鲍曼不动杆菌临床分离株的临床前药理学特征,包括26株抗生素敏感(S-AB)、8株多重耐药(MDR-AB)和203株碳青霉烯耐药(CR-AB)。与单用SCF治疗相比,联合治疗224例(94.51%)有增效作用,10例(4.22%)等效,3例(1.27%)无相互作用。时间杀伤试验、细菌负荷定量和小鼠感染模型一致地验证了这些发现,尽管钙浓度和pH梯度发生变化,但治疗效果仍然稳定。谷氨酰胺减缓SCF耐药的发展,延长抗生素后效应,并降低突变频率。从机制上讲,谷氨酰胺将细菌代谢从抗生素耐药状态重新编程为抗生素敏感状态,从而增强活性氧(ROS)的产生,这与增加的药物摄取相结合,从而增强SCF的杀伤。这种加速的药物内流超过了外排泵和酶降解介导的清除能力,导致通过与ROS协同作用增加细菌根除。这些发现表明,协同组合具有开发耐多药抗体和CR-AB候选治疗药物的潜力。
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来源期刊
ACS Infectious Diseases
ACS Infectious Diseases CHEMISTRY, MEDICINALINFECTIOUS DISEASES&nb-INFECTIOUS DISEASES
CiteScore
9.70
自引率
3.80%
发文量
213
期刊介绍: ACS Infectious Diseases will be the first journal to highlight chemistry and its role in this multidisciplinary and collaborative research area. The journal will cover a diverse array of topics including, but not limited to: * Discovery and development of new antimicrobial agents — identified through target- or phenotypic-based approaches as well as compounds that induce synergy with antimicrobials. * Characterization and validation of drug target or pathways — use of single target and genome-wide knockdown and knockouts, biochemical studies, structural biology, new technologies to facilitate characterization and prioritization of potential drug targets. * Mechanism of drug resistance — fundamental research that advances our understanding of resistance; strategies to prevent resistance. * Mechanisms of action — use of genetic, metabolomic, and activity- and affinity-based protein profiling to elucidate the mechanism of action of clinical and experimental antimicrobial agents. * Host-pathogen interactions — tools for studying host-pathogen interactions, cellular biochemistry of hosts and pathogens, and molecular interactions of pathogens with host microbiota. * Small molecule vaccine adjuvants for infectious disease. * Viral and bacterial biochemistry and molecular biology.
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