Mechanisms of resistance to delamanid, a drug for Mycobacterium tuberculosis
Mechanisms of resistance to delamanid, a drug for Mycobacterium tuberculosis
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DOI：
10.1016/j.tube.2017.12.006
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发表时间：
2018-01-01
期刊：
影响因子：
3.2
通讯作者：
Matsumoto, Makoto
中科院分区：
文献类型：
--
作者：
Fujiwara, Mamoru;Kawasaki, Masanori;Matsumoto, Makoto
Delamanid是一种双环的硝基咪唑类化合物，对结核分枝杆菌有有效的治疗作用。先前的研究表明，对双环亚硝咪唑恶嗪PA-824的耐药性是由依赖F-420的生物激活途径的突变引起的。我们调查了是否同样的机制导致了对地拉曼德的耐药性。用卡介苗(BCG)和结核分枝杆菌H37Rv测定自发耐药性频率。研究了耐地拉曼的卡介苗菌落和两株已鉴定的结核分枝杆菌临床分离株匀浆的F-420高效液相色谱(HPLC)洗脱模式，并对依赖于F-420的生物激活途径中的基因进行了测序。对地拉曼的自发耐药率与异烟肼和PA-824相似。观察到四种不同的F-420高效液相洗脱模式，对应于在fgd1、fbiA、fbiB和fbIC上发生突变的菌落，而野生型的DDN突变体没有变化。与突变基因的野生型序列互补，恢复了敏感性。这两株对地拉曼耐药的临床分离株具有DDN突变和野生型F-420高效液相洗脱模式。总之，在依赖于F-420的生物激活途径中的5个基因中有一个基因发生了突变，具有不同的F-420高效液相洗脱模式。在建立Delamanid的快速药敏试验时，可以考虑遗传和表型变化。
Delamanid, a bicyclic nitroimidazooxazole, is effective against M. tuberculosis. Previous studies have shown that resistance to a bicyclic nitroimidazooxazine, PA-824, is caused by mutations in an F-420-dependent bio-activation pathway. We investigated whether the same mechanisms are responsible for resistance to delamanid. Spontaneous resistance frequencies were determined using M. bovis BCG Tokyo (BCG) and M. tuberculosis H37Rv. F-420 high-performance liquid chromatography (HPLC) elution patterns of homogenates of delamanid-resistant BCG colonies and two previously identified delamanid-resistant M. tuberculosis clinical isolates were examined, followed by sequencing of genes in the F-420-dependent bio-activation pathway. Spontaneous resistance frequencies to delamanid were similar to those of isoniazid and PA-824. Four distinct F-420 HPLC elution patterns were observed, corresponding to colonies with mutations on fgd1, fbiA, fbiB, and fbiC with no change in the ddn mutants from the wildtype. Complementation with the wildtype sequence of the mutated gene restored susceptibility. The two delamanid-resistant clinical isolates had ddn mutations and the wildtype F-420 HPLC elution pattern. In conclusion, delamanid-resistant bacilli have mutations in one of the 5 genes in the F-420-dependent bio-activation pathway with distinct F-420 HPLC elution patterns. Both genetic and phenotypic changes may be considered in the development of a rapid susceptibility test for delamanid.