Acquired Resistance of Mycobacterium tuberculosis to Bedaquiline

被引：306

作者：

Andries, Koen ^{[1
]}

Villellas, Cristina ^{[1
]}

Coeck, Nele ^{[2
]}

Thys, Kim ^{[1
]}

Gevers, Tom ^{[1
]}

Vranckx, Luc ^{[1
]}

Lounis, Nacer ^{[1
]}

de Jong, Bouke C. ^{[2
]}

Koul, Anil ^{[1
]}

机构：

[1] Janssen Pharmaceut, Dept Infect Dis, B-2340 Beerse, Belgium

[2] Inst Trop Med, Dept Biomed Sci, B-2000 Antwerp, Belgium

来源：

PLOS ONE | 2014年 / 9卷 / 07期

关键词：

DRUG-RESISTANCE; ATP SYNTHASE; EFFLUX; INHIBITOR; EMERGENCE; VERAPAMIL; TMC207; 1ST;

D O I：

10.1371/journal.pone.0102135

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Bedaquiline (BDQ), an ATP synthase inhibitor, is the first drug to be approved for treatment of multi-drug resistant tuberculosis in decades. In vitro resistance to BDQ was previously shown to be due to target-based mutations. Here we report that non-target based resistance to BDQ, and cross-resistance to clofazimine (CFZ), is due to mutations in Rv0678, a transcriptional repressor of the genes encoding the MmpS5-MmpL5 efflux pump. Efflux-based resistance was identified in paired isolates from patients treated with BDQ, as well as in mice, in which it was confirmed to decrease bactericidal efficacy. The efflux inhibitors verapamil and reserpine decreased the minimum inhibitory concentrations of BDQ and CFZ in vitro, but verapamil failed to increase the bactericidal effect of BDQ in mice and was unable to reverse efflux-based resistance in vivo. Cross-resistance between BDQ and CFZ may have important clinical implications.

引用

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