Identification of a small molecule with activity against drug-resistant and persistent tuberculosis

被引：181

作者：

Wang, Feng ^{[1
,2
,3
]}

Sambandan, Dhinakaran ^{[4
]}

Halder, Rajkumar ^{[1
,2
]}

Wang, Jianing ^{[1
,2
]}

Batt, Sarah M. ^{[5
]}

Weinrick, Brian ^{[4
]}

Ahmad, Insha ^{[1
,2
]}

Yang, Pengyu ^{[1
,2
]}

Zhang, Yong ^{[1
,2
]}

Kim, John ^{[4
]}

Hassani, Morad ^{[4
]}

Huszar, Stanislav ^{[6
]}

Trefzer, Claudia ^{[7
]}

Ma, Zhenkun ^{[8
]}

Kaneko, Takushi ^{[8
]}

Mdluli, Khisi E. ^{[8
]}

Franzblau, Scott ^{[9
]}

Chatterjee, Arnab K. ^{[3
]}

Johnson, Kai ^{[7
]}

Mikusova, Katarina ^{[6
]}

Besra, Gurdyal S. ^{[5
]}

Fuetterer, Klaus ^{[5
]}

Jacobs, William R., Jr. ^{[4
]}

Schultz, Peter G. ^{[1
,2
,3
]}

机构：

[1] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA

[2] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA

[3] Calif Inst Biomed Res, La Jolla, CA 92037 USA

[4] Yeshiva Univ Albert Einstein Coll Med, Howard Hughes Med Inst, Dept Microbiol & Immunol, Bronx, NY 10461 USA

[5] Univ Birmingham, Sch Biosci, Birmingham B15 2TT, W Midlands, England

[6] Comenius Univ, Fac Nat Sci, Dept Biochem, Bratislava 84215, Slovakia

[7] Ecole Polytech Fed Lausanne, Inst Bioengn, Inst Chem Sci & Engn ISIC, CH-1015 Lausanne, Switzerland

[8] Global Alliance TB Drug Dev, New York, NY 10005 USA

[9] Univ Illinois, Coll Pharm, Inst TB Res, Chicago, IL 60612 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2013年 / 110卷 / 27期

基金：

美国国家卫生研究院;

关键词：

drug resistance; dual mechanism; MYCOBACTERIUM-TUBERCULOSIS; INHIBITORS; MODEL; BIOSYNTHESIS; TOLERANT; GROWTH;

D O I：

10.1073/pnas.1309171110

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：

A cell-based phenotypic screen for inhibitors of biofilm formation in mycobacteria identified the small molecule TCA1, which has bactericidal activity against both drug-susceptible and -resistant Mycobacterium tuberculosis (Mtb) and sterilizes Mtb in vitro combined with rifampicin or isoniazid. In addition, TCA1 has bactericidal activity against nonreplicating Mtb in vitro and is efficacious in acute and chronic Mtb infection mouse models both alone and combined with rifampicin or isoniazid. Transcriptional analysis revealed that TCA1 down-regulates genes known to be involved in Mtb persistence. Genetic and affinity-based methods identified decaprenyl-phosphoryl-beta-D-ribofuranose oxidoreductase DprE1 and MoeW, enzymes involved in cell wall and molybdenum cofactor biosynthesis, respectively, as targets responsible for the activity of TCA1. These in vitro and in vivo results indicate that this compound functions by a unique mechanism and suggest that TCA1 may lead to the development of a class of antituberculosis agents.

引用

页码：E2510 / E2517

页数：8