Staphylococcus aureus Metabolic Adaptations during the Transition from a Daptomycin Susceptibility Phenotype to a Daptomycin Nonsusceptibility Phenotype
Staphylococcus aureus Metabolic Adaptations during the Transition from a Daptomycin Susceptibility Phenotype to a Daptomycin Nonsusceptibility Phenotype
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DOI：
10.1128/aac.00160-15
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发表时间：
2015-07-01
影响因子：
4.9
通讯作者：
Somerville, Greg A.
中科院分区：
文献类型：
--
作者：
Gaupp, Rosmarie;Lei, Shulei;Somerville, Greg A.
金黄色葡萄球菌是医院和社区获得性感染的主要原因。S.金黄色葡萄球菌作为病原体部分是由于其许多毒力决定因素和对抗微生物剂的抗性。特别是耐甲氧西林的S.金黄色葡萄球菌已成为感染的主要原因，并导致抗生素万古霉素和达托霉素的使用增加，这增加了万古霉素中间体S的分离。金黄色葡萄球菌和达托霉素不敏感的S.金黄色葡萄球菌S.金黄色葡萄球菌获得对抗生素的中间抗性是通过适应其生理学和代谢以允许在这些抗生素存在下生长，这一过程称为适应性抗性。为了更好地了解与适应性抗性相关的生理和代谢变化，检查了6个达托霉素敏感和非敏感的等基因株对的生长、竞争适应性和代谢改变的变化。有趣的是，达托霉素不敏感性与向指数后生长期的过渡稍微延迟和代谢改变相一致。具体而言，达托霉素不敏感菌株具有降低的三羧酸循环活性，这与嘧啶和嘌呤的合成增加以及与壁磷壁酸和肽聚糖生物合成相关的途径的碳流增加相关。重要的是，这些数据提供了通过操纵细菌代谢来改变达托霉素不敏感表型的机会，这是开发可与达托霉素联合使用以减少治疗失败的靶向代谢途径的化合物的第一步。
Staphylococcus aureus is a major cause of nosocomial and community-acquired infections. The success of S. aureus as a pathogen is due in part to its many virulence determinants and resistance to antimicrobials. In particular, methicillin-resistant S. aureus has emerged as a major cause of infections and led to increased use of the antibiotics vancomycin and daptomycin, which has increased the isolation of vancomycin-intermediate S. aureus and daptomycin-nonsusceptible S. aureus strains. The most common mechanism by which S. aureus acquires intermediate resistance to antibiotics is by adapting its physiology and metabolism to permit growth in the presence of these antibiotics, a process known as adaptive resistance. To better understand the physiological and metabolic changes associated with adaptive resistance, six daptomycin-susceptible and -nonsusceptible isogenic strain pairs were examined for changes in growth, competitive fitness, and metabolic alterations. Interestingly, daptomycin nonsusceptibility coincides with a slightly delayed transition to the postexponential growth phase and alterations in metabolism. Specifically, daptomycin-nonsusceptible strains have decreased tricarboxylic acid cycle activity, which correlates with increased synthesis of pyrimidines and purines and increased carbon flow to pathways associated with wall teichoic acid and peptidoglycan biosynthesis. Importantly, these data provided an opportunity to alter the daptomycin nonsusceptibility phenotype by manipulating bacterial metabolism, a first step in developing compounds that target metabolic pathways that can be used in combination with daptomycin to reduce treatment failures.