Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou University, Yangzhou, China.
Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, China.
mSystems. 2024 Oct 22;9(10):e0079724. doi: 10.1128/msystems.00797-24. Epub 2024 Sep 10.
Antimicrobial resistance is rapidly increasing worldwide, highlighting the urgent need for pharmaceutical and nonpharmaceutical interventions to tackle different-to-treat bacterial infections. Tigecycline, a semi-synthesis glycylcycline for parenteral administration, is widely recognized as one of the few effective therapies available against pan-drug resistant Gram-negative pathogens. Regrettably, the efficacy of multiple drugs, including tigecycline, is currently being undermined due to the emergence of a recently discovered mobilized resistance-nodulation-division-type efflux pump gene cluster . Herein, by employing untargeted metabolomic approaches, we reveal that the expression of disrupts bacterial purine metabolism, with inosine being identified as a crucial biomarker. Notably, the supplementation of inosine effectively reverses tigecycline resistance in -positive bacteria. Mechanistically, exogenous inosine enhanced bacterial proton motive force, which promotes the uptake of tigecycline. Furthermore, inosine enhances succinate biosynthesis by stimulating the tricarboxylic acid cycle. Succinate interacts with the two-component system EnvZ/OmpR and upregulates OmpK 36, thereby promoting the influx of tigecycline. These actions collectively lead to the increased intracellular accumulation of tigecycline. Overall, our study offers a distinct combinational strategy to manage infections caused by -positive bacteria.
TMexCD1-TOprJ1, a mobilized resistance-nodulation-division-type efflux pump, confers phenotypic resistance to multiple classes of antibiotics. Nowadays, has disseminated among diverse species of clinical pathogens, exacerbating the need for novel anti-infective strategies. In this study, we report that -negative and -positive bacteria exhibit significantly different metabolic flux and characteristics, especially in purine metabolism. Intriguingly, the addition of inosine, a purine metabolite, effectively restores the antibacterial activity of tigecycline by promoting antibiotic uptake. Our findings highlight the correlation between bacterial mechanism and antibiotic resistance, and offer a distinct approach to overcome -mediated multidrug resistance.
TMexCD1-TOprJ1 是一种可移动的抗性-结节-分裂型外排泵，它赋予了多种抗生素类别的表型耐药性。如今，这种外排泵已经在不同种类的临床病原体中传播，这加剧了对新型抗感染策略的需求。在这项研究中，我们报告称，阴性和阳性细菌表现出明显不同的代谢通量和特征，特别是在嘌呤代谢方面。有趣的是，添加嘌呤代谢物肌苷可通过促进抗生素摄取来有效恢复替加环素的抗菌活性。我们的研究结果强调了细菌机制与抗生素耐药性之间的相关性，并提供了一种克服 TMexCD1-TOprJ1 介导的多药耐药性的独特方法。
