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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Chemical Genetic Interaction Profiling Reveals Determinants of Intrinsic Antibiotic Resistance in Mycobacterium tuberculosis
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Chemical Genetic Interaction Profiling Reveals Determinants of Intrinsic Antibiotic Resistance in Mycobacterium tuberculosis

机译：化学遗传相互作用分析揭示了结核分枝杆菌中固有抗生素抗性的决定因素

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摘要

Chemotherapy for tuberculosis (TB) is lengthy and could benefit from synergistic adjuvant therapeutics that enhance current and novel drug regimens. To identify genetic determinants of intrinsic antibiotic susceptibility in Mycobacterium tuberculosis, we applied a chemical genetic interaction (CGI) profiling approach. We screened a saturated transposon mutant library and identified mutants that exhibit altered fitness in the presence of partially inhibitory concentrations of rifampin, ethambutol, isoniazid, vancomycin, and meropenem, antibiotics with diverse mechanisms of action. This screen identified the M. tuberculosis cell envelope to be a major determinant of antibiotic susceptibility but did not yield mutants whose increase in susceptibility was due to transposon insertions in genes encoding efflux pumps. Intrinsic antibiotic resistance determinants affecting resistance to multiple antibiotics included the peptidoglycan-arabinogalactan ligase Lcp1, the mycolic acid synthase MmaA4, the protein translocase SecA2, the mannosyltransferase PimE, the cell envelopeassociated protease CaeA/Hip1, and FecB, a putative iron dicitrate-binding protein. Characterization of a deletion mutant confirmed FecB to be involved in the intrinsic resistance to every antibiotic analyzed. In contrast to its predicted function, FecB was dispensable for growth in low-iron medium and instead functioned as a critical mediator of envelope integrity.
机译：结核病（TB）的化疗较长，可以从协同佐剂治疗中受益，增强电流和新型药物方案。为了鉴定结核分枝杆菌内部抗生素易感性的遗传决定因素，我们应用了化学遗传相互作用（CGI）分析方法。我们筛选了饱和的转座子突变体文库和鉴定的突变体，其在存在部分抑制浓度的利福平，乙胺醇，异烟肼，万古霉素和梅洛涅姆，抗生素具有不同的作用机制的情况下，具有改变的适应性。该筛选鉴定了抗生素敏感性的M.结核病细胞包膜，但没有产生易感性增加的突变体是由于编码Efflux泵的基因中的转座子插入。确切的抗生素抗性决定簇对多种抗生素的抗性包括肽聚糖 - 阿拉伯半乳酰变酶LCP1，氰酸合酶MMAA4，蛋白质转移酶SECA2，甘露糖基转移酶PIME，细胞包络酶分子酶CAEA / HIP1，以及FECB，一种推定的铁硝酸铁结合蛋白。缺失突变体的表征证实FECB参与了对分析的每一种抗生素的内在抗性。与其预测的功能相比，FECB可分配低铁介质的生长，而是作为封套完整性的临界介体作用。

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