Expression Dysregulation as a Mediator of Fitness Costs in Antibiotic Resistance.
Expression Dysregulation as a Mediator of Fitness Costs in Antibiotic Resistance.
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表达失调是抗生素耐药性中适应性成本的介体。
DOI：
10.1128/aac.00504-21
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发表时间：
2021-08-17
影响因子：
4.9
通讯作者：
Gagneux S
中科院分区：
文献类型：
--
作者：
Trauner A;Banaei-Esfahani A;Gygli SM;Warmer P;Feldmann J;Zampieri M;Borrell S;Collins BC;Beisel C;Aebersold R;Gagneux S
抗生素耐药性（AMR）对全球健康和经济构成威胁。利福平耐药结核分枝杆菌占全球AMR负担的三分之一。在AMR上占上风需要更深入地了解耐药性的生理学。AMR通常在没有药物的情况下导致健身成本。确定支撑这种成本的分子机制可能有助于加强未来的治疗方案。在这里，我们使用了M的集合。结核菌株提供了利福平耐药性的进化和系统发育快照，并对其进行全基因组转录组和蛋白质组分析，以确定正常生理学的关键扰动。我们发现，临床上最常见的利福平耐药突变，RpoB Ser450Leu，赋予相当大的基因表达的变化，其中许多是减轻了RpoC Leu516Pro的补偿突变。然而，我们的数据也提供了普遍的上位性的证据，相同的耐药突变施加了不同的健身成本和功能不同的基因表达在遗传无关的临床菌株的变化。最后，我们报告了一个可能的转录后调节基因表达，这是在大多数的测试菌株携带RpoB Ser450Leu共享，从而增加了丰富的蛋白质参与中央碳代谢。这些变化有助于更普遍的趋势，其中蛋白质组的组成的破坏与不同菌株中RpoB Ser450Leu突变的适应性成本相关。
Antimicrobial resistance (AMR) poses a threat to global health and the economy. Rifampicin-resistant Mycobacterium tuberculosis accounts for a third of the global AMR burden. Gaining the upper hand on AMR requires a deeper understanding of the physiology of resistance. AMR often results in a fitness cost in the absence of drug. Identifying the molecular mechanisms underpinning this cost could help strengthen future treatment regimens. Here, we used a collection of M. tuberculosis strains that provide an evolutionary and phylogenetic snapshot of rifampicin resistance and subjected them to genome-wide transcriptomic and proteomic profiling to identify key perturbations of normal physiology. We found that the clinically most common rifampicin resistance-conferring mutation, RpoB Ser450Leu, imparts considerable gene expression changes, many of which are mitigated by the compensatory mutation in RpoC Leu516Pro. However, our data also provide evidence for pervasive epistasis—the same resistance mutation imposed a different fitness cost and functionally distinct changes to gene expression in genetically unrelated clinical strains. Finally, we report a likely posttranscriptional modulation of gene expression that is shared in most of the tested strains carrying RpoB Ser450Leu, resulting in an increased abundance of proteins involved in central carbon metabolism. These changes contribute to a more general trend in which the disruption of the composition of the proteome correlates with the fitness cost of the RpoB Ser450Leu mutation in different strains.