The Genetic Background Modulates the Evolution of Fluoroquinolone-Resistance in Mycobacterium tuberculosis
The Genetic Background Modulates the Evolution of Fluoroquinolone-Resistance in Mycobacterium tuberculosis
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DOI：
10.1093/molbev/msz214
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发表时间：
2020-01-01
影响因子：
10.7
通讯作者：
Gagneux, Sebastien
中科院分区：
文献类型：
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作者：
Castro, Rhastin A. D.;Ross, Amanda;Gagneux, Sebastien
氟喹诺酮类药物（FQ）是对抗药物敏感性结核病的实验性治疗方案的主要药物。然而，很少有人知道结核分枝杆菌（Mtb）的自然群体中存在的遗传变异是否会影响耐药（EST-R）的进化。为了研究这个问题，我们使用了9个基因不同的药物敏感的结核分枝杆菌临床分离株，并测量了他们的频率的耐药性的氟喹诺酮类氧氟沙星（OFX）在体外。我们发现，Mtb遗传背景导致OFX-R频率差异跨越两个数量级，并大大调节了观察到的OFX-R突变谱。此外，在体外试验表明，遗传背景也影响了最低抑制浓度和健身效果所赋予的一个给定的OFX-R突变。为了测试我们的体外工作的临床相关性，我们调查了来自临床Mtb分离株的公开可用基因组序列中Mtb-R的突变谱，并发现了大量的Mtb谱系依赖性变异性。对Mtb-R的临床和体外突变谱的比较表明，在谱系2和谱系4菌株中，Mtb-R gyrA突变事件的临床频率的变异性分别为51%和39%，可以归因于Mtb如何在体外进化Mtb-R。由于Mtb的遗传背景强烈地影响了体外Mtb-R的进化，因此我们得出结论，Mtb的遗传背景也影响了临床Mtb-R的进化。
Fluoroquinolones (FQ) form the backbone in experimental treatment regimens against drug-susceptible tuberculosis. However, little is known on whether the genetic variation present in natural populations of Mycobacterium tuberculosis (Mtb) affects the evolution of FQ-resistance (FQ-R). To investigate this question, we used nine genetically distinct drug-susceptible clinical isolates of Mtb and measured their frequency of resistance to the FQ ofloxacin (OFX) in vitro. We found that the Mtb genetic background led to differences in the frequency of OFX-resistance (OFX-R) that spanned two orders of magnitude and substantially modulated the observed mutational profiles for OFX-R. Further, in vitro assays showed that the genetic background also influenced the minimum inhibitory concentration and the fitness effect conferred by a given OFX-R mutation. To test the clinical relevance of our in vitro work, we surveyed the mutational profile for FQ-R in publicly available genomic sequences from clinical Mtb isolates, and found substantial Mtb lineage-dependent variability. Comparison of the clinical and the in vitro mutational profiles for FQ-R showed that 51% and 39% of the variability in the clinical frequency of FQ-R gyrA mutation events in Lineage 2 and Lineage 4 strains, respectively, can be attributed to how Mtb evolves FQ-R in vitro. As the Mtb genetic background strongly influenced the evolution of FQ-R in vitro, we conclude that the genetic background of Mtb also impacts the evolution of FQ-R in the clinic.