PA-824 Kills Nonreplicating Mycobacterium tuberculosis by Intracellular NO Release

被引：516

作者：

Singh, Ramandeep ^{[1
]}

Manjunatha, Ujjini ^{[1
,2
]}

Boshoff, Helena I. M. ^{[1
]}

Ha, Young Hwan ^{[1
]}

Niyomrattanakit, Pornwaratt ^{[2
]}

Ledwidge, Richard ^{[1
]}

Dowd, Cynthia S. ^{[1
]}

Lee, Ill Young ^{[1
]}

Kim, Pilho ^{[1
]}

Zhang, Liang ^{[1
]}

Kang, Sunhee ^{[1
]}

Keller, Thomas H. ^{[2
]}

Jiricek, Jan ^{[2
]}

Barry, Clifton E., III ^{[1
]}

机构：

[1] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA

[2] Novartis Inst Trop Dis, Singapore 138670, Singapore

来源：

SCIENCE | 2008年 / 322卷 / 5906期

基金：

英国惠康基金;

关键词：

D O I：

10.1126/science.1164571

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：

Bicyclic nitroimidazoles, including PA- 824, are exciting candidates for the treatment of tuberculosis. These prodrugs require intracellular activation for their biological function. We found that Rv3547 is a deazaflavin- dependent nitroreductase ( Ddn) that converts PA- 824 into three primary metabolites; the major one is the corresponding des- nitroimidazole ( des- nitro). When derivatives of PA- 824 were used, the amount of des- nitro metabolite formed was highly correlated with anaerobic killing of Mycobacterium tuberculosis ( Mtb). Des- nitro metabolite formation generated reactive nitrogen species, including nitric oxide ( NO), which are the major effectors of the anaerobic activity of these compounds. Furthermore, NO scavengers protected the bacilli from the lethal effects of the drug. Thus, these compounds may act as intracellular NO donors and could augment a killing mechanism intrinsic to the innate immune system.

引用

页码：1392 / 1395

页数：4

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