Discovery of a Novel Mycobacterial F-ATP Synthase Inhibitor and its Potency in Combination with Diarylquinolines

被引：40

作者：

Hotra, Adam ^{[1
,2
,3
]}

Ragunathan, Priya ^{[2
]}

Ng, Pearly Shuyi ^{[4
]}

Seankongsuk, Pattarakiat ^{[1
]}

Harikishore, Amaravadhi ^{[1
,2
]}

Sarathy, Jickky Palmae ^{[5
]}

Saw, Wuan-Geok ^{[2
]}

Lakshmanan, Umayal ^{[4
]}

Sae-Lao, Patcharaporn ^{[1
]}

Kalia, Nitin Pal ^{[6
]}

Shin, Joon ^{[2
]}

Kalyanasundaram, Revathy ^{[7
]}

Anbarasu, Sivaraj ^{[7
]}

Parthasarathy, Krupakar ^{[7
]}

Pradeep, Chaudhari Namrata ^{[2
]}

Makhija, Harshyaa ^{[2
]}

Droege, Peter ^{[2
]}

Poulsen, Anders ^{[4
]}

Tan, Jocelyn Hui Ling ^{[4
]}

Pethe, Kevin ^{[2
,6
]}

Dick, Thomas ^{[5
,8
]}

Bates, Roderick W. ^{[1
]}

Grueber, Gerhard ^{[2
]}

机构：

[1] Nanyang Technol Univ, Sch Phys & Math Sci, 21 Nanyang Link, Singapore 637371, Singapore

[2] Nanyang Technol Univ, Sch Biol Sci, 60 Nanyang Dr, Singapore 637551, Singapore

[3] Nanyang Technol Univ, Interdisciplinary Grad Sch, Nanyang Inst Technol Hlth & Med, Singapore, Singapore

[4] ASTAR, Agcy Sci Technol & Res, Expt Drug Dev Ctr, 10 Biopolis Rd, Singapore 138670, Singapore

[5] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Microbiol & Immunol, 14 Med Dr, Singapore 117599, Singapore

[6] Nanyang Technol Univ, Lee Kong Chian Sch Med, Expt Med Bldg, Singapore, Singapore

[7] Sathyabama Inst Sci & Technol, Ctr Drug Discovery & Dev, Chennai 600119, Tamil Nadu, India

[8] Hackensack Meridian Hlth, Ctr Discovery & Innovat, 40 Kingsland St, Nutley, NJ 07110 USA

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2020年 / 59卷 / 32期

基金：

新加坡国家研究基金会;

关键词：

ATP synthesis; drug discovery; inhibitors; F-ATP synthase; tuberculosis; TUBERCULOSIS DRUG BEDAQUILINE; SUBUNIT EPSILON; ANALOGS; RESISTANCE;

D O I：

10.1002/anie.202002546

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

The F1FO-ATP synthase is required for growth and viability of Mycobacterium tuberculosis and is a validated clinical target. A mycobacterium-specific loop of the enzyme's rotary gamma subunit plays a role in the coupling of ATP synthesis within the enzyme complex. We report the discovery of a novel antimycobacterial, termed GaMF1, that targets this gamma subunit loop. Biochemical and NMR studies show that GaMF1 inhibits ATP synthase activity by binding to the loop. GaMF1 is bactericidal and is active against multidrug- as well as bedaquiline-resistant strains. Chemistry efforts on the scaffold revealed a dynamic structure activity relationship and delivered analogues with nanomolar potencies. Combining GaMF1 with bedaquiline or novel diarylquinoline analogues showed potentiation without inducing genotoxicity or phenotypic changes in a human embryonic stem cell reporter assay. These results suggest that GaMF1 presents an attractive lead for the discovery of a novel class of anti-tuberculosis F-ATP synthase inhibitors.

引用

页码：13295 / 13304

页数：10

共 43 条

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