State Key Laboratory of Tropical Oceanography, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510301, China.
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, China.
J Proteome Res. 2024 Oct 4;23(10):4480-4494. doi: 10.1021/acs.jproteome.4c00381. Epub 2024 Sep 18.
Antibiotic resistance is a major global challenge requiring new treatments and a better understanding of the bacterial resistance mechanisms. In this study, we compared ampicillin-resistant (R-AMP) and gentamicin-resistant (R-GEN) strains with a sensitive strain (ATCC6538) using metabolomics. We identified 109 metabolites; 28 or 31 metabolites in R-AMP or R-GEN differed from those in ATCC6538. Moreover, R-AMP and R-GEN were enriched in five and four pathways, respectively. R-AMP showed significantly up-regulated amino acid metabolism and down-regulated energy metabolism, whereas R-GEN exhibited an overall decrease in metabolism, including carbohydrate, energy, and amino acid metabolism. Furthermore, the activities of the metabolism-related enzymes pyruvate dehydrogenase and TCA cycle dehydrogenases were inhibited in antibiotic-resistant bacteria. Significant decreases in NADH and ATP levels were also observed. In addition, the arginine biosynthesis pathway, which is related to nitric oxide (NO) production, was enriched in both antibiotic-resistant strains. Enhanced NO synthase activity in promoted NO production, which further reduced reactive oxygen species, mediating the development of bacterial resistance to ampicillin and gentamicin. This study reveals that bacterial resistance affects metabolic profile, and changes in energy metabolism and arginine biosynthesis are important factors leading to drug resistance in .
抗生素耐药性是一个全球性的重大挑战，需要新的治疗方法和更好地了解细菌耐药机制。在这项研究中，我们使用代谢组学比较了氨苄青霉素耐药（R-AMP）和庆大霉素耐药（R-GEN）菌株与敏感菌株（ATCC6538）的差异。我们鉴定出 109 种代谢物；R-AMP 或 R-GEN 中有 28 或 31 种代谢物与 ATCC6538 不同。此外，R-AMP 和 R-GEN 分别富集了五个和四个途径。R-AMP 表现出显著上调的氨基酸代谢和下调的能量代谢，而 R-GEN 则表现出整体代谢下降，包括碳水化合物、能量和氨基酸代谢。此外，抗生素耐药菌中的代谢相关酶丙酮酸脱氢酶和 TCA 循环脱氢酶的活性受到抑制。还观察到 NADH 和 ATP 水平的显著降低。此外，与一氧化氮（NO）产生相关的精氨酸生物合成途径在两种抗生素耐药菌株中均富集。增强的一氧化氮合酶活性促进了 NO 的产生，进一步降低了活性氧，介导了细菌对氨苄青霉素和庆大霉素耐药性的发展。这项研究表明，细菌耐药性会影响代谢谱，能量代谢和精氨酸生物合成的变化是导致细菌对氨苄青霉素和庆大霉素耐药的重要因素。
