The increasing spread of antibiotic resistant bacteria is a major human health concern. The challenging development of new effective antibiotics has led to focus on seeking synergistic antibiotic combinations. Vancomycin (VAN) is a glycopeptide antibiotic used to treat Staphylococcus aureus and enterococci infections. It is targeting D-Alanyl-D-Alanine dimers during peptidoglycan biosynthesis. D-cycloserine (DCS) is a D-Alanine analogue that targets peptidoglycan biosynthesis by inhibiting D-Alanine:D-Alanine ligase (Ddl). The VAN-DCS combination was found to be synergistic in VAN resistant S. aureus strains lacking van genes cluster. We hypothesize that this combination leads to opposite effects in S. aureus and enterococci strains harboring van genes cluster where VAN resistance is conferred by the synthesis of modified peptidoglycan precursors ending in D-Alanyl-D-Lactate. The calculated Fractional Inhibitory Concentration of VAN-DCS combination in a van- vancomycin-intermediate, VanA type, and VanB type strains were 0.5, 5 and 3, respectively. As a result, VAN-DCS combination leads to synergism in van-lacking strains, and to antagonism in strains harboring van genes cluster. The VAN-DCS antagonism is due to a mechanism that we named van-mediated Ddl inhibition bypass. Our results show that antibiotic combinations can lead to opposite effects depending on the genetic backgrounds.

中文翻译：

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万古霉素和D-环丝氨酸组合对万古霉素耐药的金黄色葡萄球菌和肠球菌的作用相反。

抗生素抗性细菌的日益扩散是人类主要的健康问题。新型有效抗生素具有挑战性的发展已导致人们集中精力寻找协同作用的抗生素组合。万古霉素（VAN）是一种糖肽抗生素，用于治疗金黄色葡萄球菌和肠球菌感染。它在肽聚糖生物合成过程中靶向D-丙氨酰-D-丙氨酸二聚体。D-环丝氨酸（DCS）是一种D-丙氨酸类似物，可通过抑制D-丙氨酸：D-丙氨酸连接酶（Ddl）靶向肽聚糖的生物合成。发现VAN-DCS组合在缺乏van基因簇的VAN抗性金黄色葡萄球菌菌株中是协同的。我们假设这种组合会在S中产生相反的作用。带有van基因簇的金黄色葡萄球菌和肠球菌菌株，通过合成以D-丙氨酰-D-乳酸酯结尾的修饰的肽聚糖前体，赋予VAN抗性。在万古霉素中间体，VanA型和VanB型菌株中，VAN-DCS组合的计算分数抑制浓度分别为0.5、5和3。结果，VAN-DCS组合在缺乏van的菌株中导致协同作用，并在具有van基因簇的菌株中产生拮抗作用。VAN-DCS拮抗作用是由于我们将其命名为van介导的Ddl抑制旁路。我们的结果表明，抗生素组合可导致相反的作用，具体取决于遗传背景。和VanB型菌株分别为0.5、5和3。结果，VAN-DCS组合在缺乏van的菌株中导致协同作用，并在具有van基因簇的菌株中产生拮抗作用。VAN-DCS拮抗作用是由于我们将其称为van介导的Ddl抑制旁路的机制所致。我们的结果表明，抗生素组合可导致相反的作用，具体取决于遗传背景。和VanB型菌株分别为0.5、5和3。结果，VAN-DCS组合在缺乏van的菌株中导致协同作用，并在具有van基因簇的菌株中产生拮抗作用。VAN-DCS拮抗作用是由于我们将其称为van介导的Ddl抑制旁路的机制所致。我们的结果表明，抗生素组合可导致相反的作用，具体取决于遗传背景。