Viridans group streptococci of the Streptococcus mitis-oralis subgroup are important endovascular pathogens. They can rapidly develop high-level and durable non-susceptibility to daptomycin both in vitro and in vivo upon exposure to daptomycin. Two consistent genetic adaptations associated with this phenotype (i.e., mutations in cdsA and pgsA) lead to the depletion of the phospholipids, phosphatidylglycerol and cardiolipin, from the bacterial membrane. Such alterations in phospholipid biosynthesis will modify carbon flow and change the bacterial metabolic status. To determine the metabolic differences between daptomycin-susceptible and non-susceptible bacteria, the physiology and metabolomes of S. mitis-oralis strains 351 (daptomycin-susceptible) and 351-D10 (daptomycin non-susceptible) were analyzed. S. mitis-oralis strain 351-D10 was made daptomycin non-susceptible through serial passage in the presence of daptomycin. Daptomycin non-susceptible S. mitis-oralis had significant alterations in glucose catabolism and a re-balancing of the redox status through amino acid biosynthesis relative to daptomycin susceptible S. mitis-oralis. These changes were accompanied by a reduced capacity to generate biomass, creating a fitness cost in exchange for daptomycin non-susceptibility. S. mitis-oralis metabolism is altered in daptomycin non-susceptible bacteria relative to the daptomycin susceptible parent strain. As demonstrated in Staphylococcus aureus, inhibiting the metabolic changes that facilitate the transition from a daptomycin susceptible state to a non-susceptible one, inhibits daptomycin non-susceptibility. By preventing these metabolic adaptations in S. mitis-oralis, it should be possible to deter the formation of daptomycin non-susceptibility.

中文翻译：

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与口链球菌对达托霉素适应性耐药相关的代谢变化。


口链球菌亚群的草绿色群链球菌是重要的血管内病原体。在接触达托霉素后，它们可以在体外和体内迅速产生高水平且持久的对达托霉素的不敏感性。与该表型相关的两个一致的遗传适应（即cdsA和pgsA的突变）导致细菌膜上磷脂、磷脂酰甘油和心磷脂的消耗。磷脂生物合成的这种改变将改变碳流并改变细菌代谢状态。为了确定达托霉素敏感细菌和非敏感细菌之间的代谢差异，分析了口链霉菌菌株 351（达托霉素敏感）和 351-D10（达托霉素不敏感）的生理学和代谢组。通过在达托霉素存在下连续传代使口链球菌菌株351-D10对达托霉素不敏感。相对于达托霉素敏感的S.mitis-oralis，达托霉素不敏感的S.mitis-oralis在葡萄糖分解代谢方面具有显着的改变，并且通过氨基酸生物合成重新平衡氧化还原状态。这些变化伴随着产生生物量的能力降低，产生适应成本以换取达托霉素不敏感性。相对于达托霉素敏感亲本菌株，口链球菌代谢在达托霉素不敏感细菌中发生改变。正如金黄色葡萄球菌所证明的，抑制促进从达托霉素敏感状态向不敏感状态转变的代谢变化，可以抑制达托霉素不敏感状态。通过阻止口链球菌的这些代谢适应，应该可以阻止达托霉素不敏感性的形成。