Desjardins Christopher A, Cohen Keira A, Munsamy Vanisha, Abeel Thomas, Maharaj Kashmeel, Walker Bruce J, Shea Terrance P, Almeida Deepak V, Manson Abigail L, Salazar Alex, Padayatchi Nesri, O'Donnell Max R, Mlisana Koleka P, Wortman Jennifer, Birren Bruce W, Grosset Jacques, Earl Ashlee M, Pym Alexander S
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Nat Genet. 2016 May;48(5):544-51. doi: 10.1038/ng.3548. Epub 2016 Apr 11.
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 such as D-cycloserine. Here we used the whole-genome sequences from 498 strains of M. tuberculosis to identify new 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 use of this toxic drug among patients with susceptible infections.
更全面地了解结核分枝杆菌耐药性的遗传基础对于及时诊断和优化治疗至关重要，尤其是对于毒性二线药物如D-环丝氨酸而言。在此，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型。通过将关联分析和相关进化测试与从罕见变异中放大信号的策略相结合，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相关。仅在多重耐药菌株中观察到这种功能丧失的趋同进化。药敏试验证实ald功能丧失赋予了对D-环丝氨酸的耐药性，并且通过ald互补部分恢复了对该药物的敏感性。在体外培养时，ald和alr发生突变的临床菌株对D-环丝氨酸的耐药性增加。将D-环丝氨酸耐药性纳入新型分子诊断中，可使这种毒性药物在易感感染患者中得到有针对性的使用。
