Genomic and functional analyses of Mycobacterium tuberculosis strains implicate ald in D-cycloserine resistance.
Genomic and functional analyses of Mycobacterium tuberculosis strains implicate ald in D-cycloserine resistance.
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DOI：
10.1038/ng.3548
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发表时间：
2016-05
期刊：
影响因子：
30.8
通讯作者：
Pym AS
中科院分区：
文献类型：
--
作者：
Desjardins CA;Cohen KA;Munsamy V;Abeel T;Maharaj K;Walker BJ;Shea TP;Almeida DV;Manson AL;Salazar A;Padayatchi N;O'Donnell MR;Mlisana KP;Wortman J;Birren BW;Grosset J;Earl AM;Pym AS
更全面地了解结核分枝杆菌耐药的遗传基础，对于及时诊断和最佳治疗至关重要，特别是对D-环丝氨酸等有毒二线药物。在这里，我们使用了498株结核分枝杆菌的全基因组序列来鉴定新的耐药基因类型。通过结合关联和相关进化测试以及从罕见变异中放大信号的策略，我们发现编码L-丙氨酸脱氢酶的ALD(Rv2780)功能缺失突变与不明原因的耐药性有关。这种功能丧失的进化仅在耐多药菌株中观察到。药敏试验证实，ALD功能丧失导致了对D-环丝氨酸的耐药性，并且通过补充ALD部分恢复了对药物的敏感性。具有ald和alr突变的临床菌株在体外培养时对D-环丝氨酸的耐药性增加。在新的分子诊断中加入D-环丝氨酸抗性可以允许在易感感染的患者中有针对性地使用这种有毒药物。
A more complete understanding of the genetic basis of drug resistance in Mycobacterium tuberculosis is critical for prompt diagnosis and optimal treatment, particularly for toxic second-line drugs like D-cycloserine. Here, we used whole-genome sequences from 498 strains of M. tuberculosis to identify novel resistance-conferring genotypes. By combining association and correlated evolution tests with strategies for amplifying signal from rare variants, we found that loss-of-function mutations in ald (Rv2780), encoding L-alanine dehydrogenase, were associated with unexplained drug resistance. Convergent evolution of this loss-of-function was observed exclusively among multidrug-resistant strains. Drug susceptibility testing established that ald loss-of-function conferred resistance to D-cycloserine, and susceptibility to the drug was partially restored by complementation of ald. Clinical strains with mutations in ald and alr exhibited increased resistance to D-cycloserine when cultured in vitro. Incorporation of D-cycloserine resistance in novel molecular diagnostics could allow for targeted utilization of this toxic drug among patients with susceptible infections.