The small-molecule SMARt751 reverses Mycobacterium tuberculosis resistance to ethionamide in acute and chronic mouse models of tuberculosis

被引：19

作者：

Flipo, Marion ^{[1
]}

Frita, Rosangela ^{[2
]}

Bourotte, Marilyne ^{[1
,3
]}

Martinez-Martinez, Maria S. ^{[4
]}

Boesche, Markus ^{[5
]}

Boyle, Gary W. ^{[6
]}

Derimanov, Geo ^{[7
]}

Drewes, Gerard ^{[5
]}

Gamallo, Pablo ^{[4
]}

Ghidelli-Disse, Sonja ^{[5
]}

Gresham, Stephanie ^{[6
]}

Jimenez, Elena ^{[4
]}

de Mercado, Jaime ^{[4
]}

Perez-Herran, Esther ^{[4
]}

Porras-De Francisco, Esther ^{[4
]}

Rullas, Joaquin ^{[4
]}

Casado, Patricia ^{[4
]}

Leroux, Florence ^{[1
,8
]}

Piveteau, Catherine ^{[1
]}

Kiass, Mehdi ^{[9
]}

Mathys, Vanessa ^{[9
]}

Soetaert, Karine ^{[9
]}

Megalizzi, Veronique ^{[10
]}

Tanina, Abdalkarim ^{[10
]}

Wintjens, Rene ^{[10
]}

Antoine, Rudy ^{[2
]}

Brodin, Priscille ^{[2
,8
]}

Delorme, Vincent ^{[2
,12
]}

Moune, Martin ^{[2
]}

Djaout, Kamel ^{[2
]}

Slupek, Stephanie ^{[2
]}

Kemmer, Christian ^{[11
]}

Gitzinger, Marc ^{[11
]}

Ballell, Lluis ^{[4
]}

Mendoza-Losana, Alfonso ^{[4
,13
]}

Lociuro, Sergio ^{[11
]}

Deprez, Benoit ^{[1
,8
]}

Barros-Aguirre, David ^{[4
]}

Remuinan, Modesto J. ^{[4
]}

Willand, Nicolas ^{[1
]}

Baulard, Alain R. ^{[2
,8
]}

机构：

[1] Univ Lille, Inst Pasteur Lille, Inserm, U1177 Drugs & Mol Living Syst, F-59000 Lille, France

[2] Univ Lille, U1019 UMR9017 CIIL Ctr Infect & Immun Lille, Inst Pasteur Lille, Inserm,CHU Lille, F-59000 Lille, France

[3] BioVersys SAS, Lille, France

[4] GSK, Tres Cantos R&D, PTM, Madrid 28760, Spain

[5] Cellzome GmbH, D-69117 Heidelberg, Germany

[6] GSK, David Jack Ctr R&D, Pk Rd, Ware SG12 ODP, Herts, England

[7] GSK, Clin Pharmacol & Expt Med, 1250 South Collegeville Rd, Collegeville, PA 19426 USA

[8] Univ Lille, Inst Pasteur Lille, US 41 UAR 2014 PLBS, Inserm,CHU Lille, F-59000 Lille, France

[9] Sciensano, Natl Reference Ctr TB & Mycobacteria, Brussels, Belgium

[10] Univ Libre Bruxelles, Fac Pharm, Microbiol Bioorgan & Macromol Chem, Brussels, Belgium

[11] BioVersys AG, Basel, Switzerland

[12] Inst Pasteur Korea, TB Res Lab, Discovery Biol, Gyeonggi Do, South Korea

[13] Univ Carlos III Madrid, Dept Bioingn & Ingn Aerosp, Madrid, Spain

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2022年 / 14卷 / 643期

基金：

欧洲研究理事会; 英国惠康基金;

关键词：

DRUG DISCOVERY; MYMA OPERON; IN-VITRO; ETHR; ACTIVATION; INHIBITORS; PHARMACOKINETICS; BOOSTERS; DESIGN; TARGET;

D O I：

10.1126/scitranslmed.aaz6280

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The sensitivity of Mycobacterium tuberculosis, the pathogen that causes tuberculosis (TB), to antibiotic prodrugs is dependent on the efficacy of the activation process that transforms the prodrugs into their active antibacterial moieties. Various oxidases of M. tuberculosis have the potential to activate the prodrug ethionamide. Here, we used medicinal chemistry coupled with a phenotypic assay to select the N-acylated 4-phenylpiperidine compound series. The lead compound, SMARt751, interacted with the transcriptional regulator VirS of M. tuberculosis, which regulates the mymA operon encoding a monooxygenase that activates ethionamide. SMARt751 boosted the efficacy of ethionamide in vitro and in mouse models of acute and chronic TB. SMARt751 also restored full efficacy of ethionamide in mice infected with M. tuberculosis strains carrying mutations in the ethA gene, which cause ethionamide resistance in the clinic. SMARt751 was shown to be safe in tests conducted in vitro and in vivo. A model extrapolating animal pharmacokinetic and pharmacodynamic parameters to humans predicted that as little as 25 mg of SMARt751 daily would allow a fourfold reduction in the dose of ethionamide administered while retaining the same efficacy and reducing side effects.

引用

页数：14