School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68588-0905, USA.
Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
J Antimicrob Chemother. 2019 Aug 1;74(8):2274-2283. doi: 10.1093/jac/dkz194.
A major developing problem in the treatment of Staphylococcus aureus infections is the emergence of resistance during treatment with daptomycin. Previous metabolomic analyses of isogenic S. aureus strains prior to and after evolution into a daptomycin non-susceptible (DapNS) state provided important metabolic information about this transition (e.g. perturbations of the tricarboxylic acid cycle).
To assess the significance of these metabolic changes, in vitro susceptibility to daptomycin was determined in daptomycin-susceptible (DapS) and DapNSS. aureus strains cultivated with metabolic inhibitors targeting these changes.
Only inhibitors that are approved for use in humans were chosen (i.e. fosfomycin, valproate, trimetazidine and 6-mercaptopurine) to assess the importance of metabolic pathways for daptomycin non-susceptibility. The ability of these inhibitors to forestall the emergence of DapNS strains was also assessed.
The combination of daptomycin and fosfomycin synergistically killed both DapS and DapNS strains in vitro and enhanced the in vivo outcome against a DapNS strain in experimental endocarditis. Interestingly, fosfomycin acts on the peptidoglycan biosynthetic enzyme UDP-N-acetylglucosamine enolpyruvyl transferase (MurA); however, it also had a significant effect on the enzymatic activity of enolase, an essential enzyme in S. aureus. While fosfomycin acted synergistically with daptomycin, it failed to prevent the in vitro evolution of daptomycin non-susceptibility. In contrast, trimetazidine, an anti-angina drug that stimulates glucose oxidation, abolished the ability of DapSS. aureus strains to transition to a DapNS state.
These data reveal that metabolic adaptations associated with DapNS strains can be targeted to prevent the emergence of and/or reverse pre-existing resistance to daptomycin.
在治疗金黄色葡萄球菌感染的过程中，一个主要的问题是在使用达托霉素治疗时会出现耐药性。之前对同源金黄色葡萄球菌在进化为达托霉素不敏感（DapNS）状态前后进行的代谢组学分析提供了关于这种转变的重要代谢信息（例如三羧酸循环的干扰）。
评估这些代谢变化的意义，测定了在达托霉素敏感（DapS）和 DapNSS 的金黄色葡萄球菌菌株中，用针对这些变化的代谢抑制剂进行体外药敏试验。
仅选择已获准用于人类的抑制剂（即磷霉素、丙戊酸钠、曲美他嗪和 6-巯基嘌呤）来评估代谢途径对达托霉素不敏感性的重要性。还评估了这些抑制剂阻止 DapNS 菌株出现的能力。
达托霉素和磷霉素联合在体外协同杀死 DapS 和 DapNS 菌株，并增强了实验性心内膜炎中对 DapNS 菌株的体内疗效。有趣的是，磷霉素作用于肽聚糖生物合成酶 UDP-N-乙酰葡萄糖胺烯醇丙酮酸转移酶（MurA）；然而，它对烯醇酶的酶活性也有显著影响，烯醇酶是金黄色葡萄球菌的一种必需酶。虽然磷霉素与达托霉素协同作用，但它未能阻止达托霉素不敏感性的体外进化。相比之下，一种刺激葡萄糖氧化的抗心绞痛药物曲美他嗪，阻止了 DapSS. 金黄色葡萄球菌菌株向 DapNS 状态转变的能力。
这些数据表明，与 DapNS 菌株相关的代谢适应可以作为靶点，以防止达托霉素耐药性的出现和/或逆转。
