Plasticity of the Mycobacterium tuberculosis respiratory chain and its impact on tuberculosis drug development

被引：90

作者：

Beites, Tiago ^{[1
]}

O'Brien, Kathryn ^{[1
]}

Tiwari, Divya ^{[1
]}

Engelhart, Curtis A. ^{[1
]}

Walters, Shaun ^{[1
,6
]}

Andrews, Jenna ^{[2
]}

Yang, Hee-Jeong ^{[2
]}

Sutphen, Michelle L. ^{[2
]}

Weiner, Danielle M. ^{[2
]}

Dayao, Emmanuel K. ^{[2
]}

Zimmerman, Matthew ^{[3
]}

Prideaux, Brendan ^{[3
]}

Desai, Prashant V. ^{[4
]}

Masquelin, Thierry ^{[4
]}

Via, Laura E. ^{[2
,5
]}

Dartois, Veronique ^{[3
]}

Boshoff, Helena I. ^{[2
]}

Barry, Clifton E., III ^{[2
,5
]}

Ehrt, Sabine ^{[1
]}

Schnappinger, Dirk ^{[1
]}

机构：

[1] Weill Cornell Med Coll, Dept Microbiol & Immunol, New York, NY 10065 USA

[2] NIAID, TB Res Sect, Lab Clin Immunol & Microbiol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

[3] Hackensack Meridian Hlth, Ctr Discovery & Innovat, Nutley, NJ 07110 USA

[4] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA

[5] Univ Cape Town, Inst Infect Dis & Mol Med, Dept Pathol, ZA-7925 Cape Town, South Africa

[6] Univ Queensland, Sch Biomed Sci, Brisbane, Qld 4072, Australia

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

基金：

比尔及梅琳达.盖茨基金会;

关键词：

II NADH DEHYDROGENASE; READ ALIGNMENT; INHIBITION; INFECTION; 1-AMINOBENZOTRIAZOLE; ADAPTATION; METABOLISM; CLEARANCE; DISCOVERY; REGIMEN;

D O I：

10.1038/s41467-019-12956-2

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：

07 ; 0710 ; 09 ;

摘要：

The viability of Mycobacterium tuberculosis (Mtb) depends on energy generated by its respiratory chain. Cytochrome bc1-aa3 oxidase and type-2 NADH dehydrogenase (NDH-2) are respiratory chain components predicted to be essential, and are currently targeted for drug development. Here we demonstrate that an Mtb cytochrome bc1-aa3 oxidase deletion mutant is viable and only partially attenuated in mice. Moreover, treatment of Mtb-infected marmosets with a cytochrome bc1-aa3 oxidase inhibitor controls disease progression and reduces lesion-associated inflammation, but most lesions become cavitary. Deletion of both NDH-2 encoding genes (Delta ndh-2 mutant) reveals that the essentiality of NDH-2 as shown in standard growth media is due to the presence of fatty acids. The Delta ndh-2 mutant is only mildly attenuated in mice and not differently susceptible to clofazimine, a drug in clinical use proposed to engage NDH-2. These results demonstrate the intrinsic plasticity of Mtb's respiratory chain, and highlight the challenges associated with targeting the pathogen's respiratory enzymes for tuberculosis drug development.

引用

页数：12

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