Zhao Xian-Liang, Chen Zhuang-Gui, Yang Tian-Ci, Jiang Ming, Wang Jie, Cheng Zhi-Xue, Yang Man-Jun, Zhu Jia-Xin, Zhang Tian-Tuo, Li Hui, Peng Bo, Peng Xuan-Xian
Third Affiliated Hospital, State Key Laboratory of Bio-Control and School of Life Sciences, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Guangdong Key Laboratory of Pharmaceutical Functional Genes, Sun Yat-sen University, Guangzhou 510275, People's Republic of China.
Laboratory for Marine Biology and Biotechnology and Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266200, People's Republic of China.
Sci Transl Med. 2021 Dec 22;13(625):eabj0716. doi: 10.1126/scitranslmed.abj0716.
The prevalence of multidrug-resistant bacteria has been increasing rapidly worldwide, a trend that poses great risk to human and animal health and creates urgent need for pharmaceutical and nonpharmaceutical approaches to stop the spread of disease due to antimicrobial resistance. Here, we found that alanine, aspartate, and glutamate metabolism was inactivated, and glutamine was repressed in multidrug-resistant uropathogenic using a comparative metabolomics approach. Exogenous glutamine promoted β-lactam–, aminoglycoside-, quinolone-, and tetracycline-induced killing of uropathogenic and potentiated ampicillin to eliminate multidrug-resistant , , , , , and . Glutamine-potentiated ampicillin-mediated killing was effective against biofilms of these bacteria in a mouse urinary tract infection model and against systemic infection caused by , , , or in a mouse model. Exogenous glutamine stimulated influx of ampicillin, leading to the accumulation of intracellular antibiotic concentrations that exceeded the amount tolerated by the multidrug-resistant bacteria. Furthermore, we demonstrated that exogenous glutamine promoted the biosynthesis of nucleosides including inosine, which in turn interacted with CpxA/CpxR and up-regulated OmpF. We validated the physiological relevance of the mechanism by showing that loss of , , , or elevated antibiotic resistance in antibiotic-sensitive strains. In addition, glutamine retarded the development of ampicillin resistance. These results may facilitate future development of effective approaches for preventing or managing chronic, multidrug-resistant bacterial infections, bacterial persistence, and difficult-to-treat bacterial biofilms.
全球范围内，多重耐药菌的流行率一直在迅速上升，这一趋势对人类和动物健康构成了巨大风险，并迫切需要采取药物和非药物方法来阻止由于抗菌药物耐药性导致的疾病传播。在此，我们使用比较代谢组学方法发现，在多重耐药尿路致病性细菌中，丙氨酸、天冬氨酸和谷氨酸代谢失活，谷氨酰胺受到抑制。外源性谷氨酰胺促进了β-内酰胺类、氨基糖苷类、喹诺酮类和四环素类药物对尿路致病性细菌的杀伤作用，并增强了氨苄西林对多重耐药菌、、、、、和的清除能力。在小鼠尿路感染模型中，谷氨酰胺增强的氨苄西林介导的杀伤作用对这些细菌的生物膜有效，在小鼠模型中对由、、或引起的全身感染也有效。外源性谷氨酰胺刺激了氨苄西林的内流，导致细胞内抗生素浓度积累，超过了多重耐药菌的耐受量。此外，我们证明外源性谷氨酰胺促进了包括肌苷在内的核苷的生物合成，肌苷进而与CpxA/CpxR相互作用并上调OmpF。我们通过显示、、或的缺失会提高抗生素敏感菌株的抗生素耐药性，验证了该机制的生理相关性。此外，谷氨酰胺延缓了氨苄西林耐药性的发展。这些结果可能有助于未来开发预防或管理慢性多重耐药细菌感染、细菌持续性感染和难治性细菌生物膜的有效方法。
