Guo Juan, Pan Zhiyu, Fan Lvyuan, Zhong Yilin, Pang Rui, Su Yubin
Department of Cell Biology & Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Provincial Key Laboratory of Bioengineering Medicine, College of Life Science and Technology, Jinan University, Guangzhou, 510632, People's Republic of China.
Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, People's Republic of China.
Infect Drug Resist. 2023 Jul 20;16:4741-4754. doi: 10.2147/IDR.S411658. eCollection 2023.
BACKGROUND: The issue of methicillin-resistant (MRSA) resistant to many antibiotics and causing serious infectious diseases is a growing healthcare concern. PURPOSE: In recent years, exogenous administration of metabolites in combination with antibiotics can re-sensitize resistant bacteria to antibiotics; however, their effects vary, and their underlying mechanism of action remains elusive. METHODS: We assessed the bactericidal effects of the three amino acids in combination with gentamicin in vitro and in vivo. Subsequently, we explored the role of these amino acids on the metabolomics of MRSA using Liquid chromatography-tandem mass spectrometry (LC-MS/MS). Furthermore, we performed the downstream analyses using MetaboAnalyst and Interactive Pathways Explorer. RESULTS: Exogenous threonine showed the best bactericidal efficacy with gentamicin, followed by glycine, wherein serine had no effect. Amino acid treatments mainly up-regulated the metabolites, increased the amino acid abundance, and significantly activated metabolisms; these effects were consistent with the bactericidal efficacy of the three amino acids. Most amino acids participated in the tricarboxylic acid cycle, and threonine supplementation increased the activities of citrate synthase, isocitrate dehydrogenase and α-ketoglutarate dehydrogenase, whereas glycine increased activities of citrate synthase and α-ketoglutarate dehydrogenase, and serine did not affect the activities of any of the three key enzymes. We identified 24 biomarkers in the three groups, among which glutamic acid and cysteine showed a gradient decrease and increase, respectively. Subsequent analyses revealed that glutamic acid but not cysteine promoted the bactericidal effect of gentamicin synergistically. CONCLUSION: Threonine has the best synergistic effect in reversing bacterial resistance compared to glycine and serine. We show that different amino acids combined with an antibiotic mainly affect amino acid metabolism and act via different metabolic regulatory mechanisms, which could help develop effective strategies for tackling MRSA infections.
背景：耐甲氧西林金黄色葡萄球菌（MRSA）对多种抗生素耐药并引发严重传染病，这一问题日益引起医疗保健领域的关注。 目的：近年来，外源性给予代谢物与抗生素联合使用可使耐药菌重新对抗生素敏感；然而，其效果各异，作用机制仍不明确。 方法：我们评估了三种氨基酸与庆大霉素联合使用在体外和体内的杀菌效果。随后，我们使用液相色谱 - 串联质谱（LC-MS/MS）探索了这些氨基酸对MRSA代谢组学的作用。此外，我们使用MetaboAnalyst和交互式通路浏览器进行了下游分析。 结果：外源性苏氨酸与庆大霉素联合使用时杀菌效果最佳，其次是甘氨酸，而丝氨酸无作用。氨基酸处理主要上调代谢物，增加氨基酸丰度，并显著激活代谢；这些效果与三种氨基酸的杀菌效果一致。大多数氨基酸参与三羧酸循环，补充苏氨酸可增加柠檬酸合酶、异柠檬酸脱氢酶和α-酮戊二酸脱氢酶的活性，而甘氨酸增加柠檬酸合酶和α-酮戊二酸脱氢酶的活性，丝氨酸对这三种关键酶的活性均无影响。我们在三组中鉴定出24种生物标志物，其中谷氨酸呈梯度下降，半胱氨酸呈梯度上升。后续分析表明，谷氨酸而非半胱氨酸协同促进了庆大霉素的杀菌作用。 结论：与甘氨酸和丝氨酸相比，苏氨酸在逆转细菌耐药性方面具有最佳协同作用。我们表明，不同氨基酸与抗生素联合主要影响氨基酸代谢，并通过不同的代谢调节机制发挥作用，这有助于制定有效的策略来应对MRSA感染。
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