IQG-607 abrogates the synthesis of mycolic acids and displays intracellular activity against Mycobacterium tuberculosis in infected macrophages

被引：24

作者：

Rodrigues-Junior, Valnes S. ^{[1
,2
,3
,4
]}

dos Santos Junior, Andre A. ^{[1
,2
,3
]}

Villela, Anne D. ^{[1
,2
,3
]}

Belardinelli, Juan M. ^{[5
]}

Morbidoni, Hector R. ^{[5
]}

Basso, Luiz A. ^{[1
,2
,3
,4
]}

Campos, Maria M. ^{[1
,2
,4
,6
]}

Santos, Diogenes S. ^{[1
,2
,3
]}

机构：

[1] Pontificia Univ Catolica Rio Grande do Sul, CPBMF, BR-90619900 Porto Alegre, RS, Brazil

[2] Pontificia Univ Catolica Rio Grande do Sul, INCT TB, BR-90619900 Porto Alegre, RS, Brazil

[3] Pontificia Univ Catolica Rio Grande do Sul, Programa Posgrad Biol Celular & Mol, BR-90619900 Porto Alegre, RS, Brazil

[4] Pontificia Univ Catolica Rio Grande do Sul, Programa Posgrad Med & Ciencias Saude, BR-90619900 Porto Alegre, RS, Brazil

[5] Univ Nacl Rosario, Catedra Microbiol, Fac Ciencias Med, RA-2000 Rosario, Santa Fe, Argentina

[6] Pontificia Univ Catolica Rio Grande do Sul, Inst Toxicol & Farmacol, BR-90619900 Porto Alegre, RS, Brazil

来源：

INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS | 2014年 / 43卷 / 01期

关键词：

Tuberculosis; Drug development; IQG-607; Mycolic acid biosynthesis inhibitor; 2-TRANS-ENOYL-ACP COA REDUCTASE; INORGANIC COMPLEX; RESISTANT TUBERCULOSIS; ENOYL REDUCTASE; WILD-TYPE; INHIBITION; MUTANT; MODEL;

D O I：

10.1016/j.ijantimicag.2013.08.021

中图分类号：

R51 [传染病];

学科分类号：

100401 ;

摘要：

In this work, the antitubercular activity of a pentacyano(isoniazid) ferrate(II) compound (IQG-607) was investigated using a macrophage model of Mycobacterium tuberculosis infection. Importantly, treatment of M.-tuberculosis-infected macrophages with IQG-607 significantly diminished the number of CFU compared with the untreated control group. The antitubercular activity of IQG-607 was similar to that observed for the positive control drugs isoniazid and rifampicin. Nevertheless, higher concentrations of IQG-607 produced a significantly greater reduction in bacterial load compared with the same concentrations of isoniazid. Analysis of the mechanism of action of IQG-607 revealed that the biosynthesis of mycolic acids was blocked. The promising activity of IQG-607 in infected macrophages and the experimental determination of its mechanism of action may help in further studies aimed at the development of a new antimycobacterial agent. (C) 2013 Elsevier B. V. and the International Society of Chemotherapy. All rights reserved.

引用

页码：82 / 85

页数：4

共 14 条

[1]

[Anonymous], WHO GLOB TUB REP 201

[2] Kinetics of inactivation of WT and C243S mutant of Mycobacterium tuberculosis enoyl reductase by activated isoniazid [J].

Basso, LA ;

Zheng, RJ ;

Blanchard, JS .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1996, 118 (45) :11301-11302

[3] An Inorganic Complex that Inhibits Mycobacterium tuberculosis Enoyl Reductase as a Prototype of a New Class of Chemotherapeutic Agents to Treat Tuberculosis [J].

Basso, Luiz A. ;

Schneider, Cristopher Z. ;

dos Santos, Anderson J. A. B. ;

dos Santos, Andre A., Jr. ;

Campos, Maria M. ;

Souto, Andre A. ;

Santos, Diogenes S. .

JOURNAL OF THE BRAZILIAN CHEMICAL SOCIETY, 2010, 21 (07) :1384-1389

[4] Mutations in the essential FAS II β-hydroxyacyl ACP dehydratase complex confer resistance to thiacetazone in Mycobacterium tuberculosis and Mycobacterium kansasii [J].

Belardinelli, Juan M. ;

Morbidoni, Hector R. .

MOLECULAR MICROBIOLOGY, 2012, 86 (03) :568-579

[5] The challenge of new drug discovery for tuberculosis [J].

Koul, Anil ;

Arnoult, Eric ;

Lounis, Nacer ;

Guillemont, Jerome ;

Andries, Koen .

NATURE, 2011, 469 (7331) :483-490

[6] Slow-onset inhibition of 2-trans-enoyl-ACP (CoA) reductase from Mycobacterium tuberculosis by an inorganic complex [J].

Oliveira, Jaim S. ;

de Sousa, Eduardo H. S. ;

de Souza, Osmar N. ;

Moreira, Icaro S. ;

Santos, Diogenes S. ;

Basso, Luiz A. .

CURRENT PHARMACEUTICAL DESIGN, 2006, 12 (19) :2409-2424

[7] An inorganic iron complex that inhibits wild-type and an isoniazid-resistant mutant 2-trans-enoyl-ACP (CoA) reductase from Mycobacterium tuberculosis [J].

Oliveira, JS ;

Sousa, EHS ;

Basso, LA ;

Palaci, M ;

Dietze, R ;

Santos, DS ;

Moreira, IS .

CHEMICAL COMMUNICATIONS, 2004, (03) :312-313

[8] Activity of IQG-607, a new orally active compound, in a murine model of Mycobacterium tuberculosis infection [J].

Rodrigues-Junior, Valnes S. ;

dos Santos Junior, Andre ;

dos Santos, Anderson Jader ;

Schneider, Cristopher Zandona ;

Calixto, Joao B. ;

Silva Sousa, Eduardo Henrique ;

de Franca Lopes, Luiz Gonzaga ;

Souto, Andre Arigony ;

Basso, Luiz Augusto ;

Santos, Diogenes Santiago ;

Campos, Maria M. .

INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS, 2012, 40 (02) :182-185

[9] Implication of purinergic P2X7 receptor in M. tuberculosis infection and host interaction mechanisms: A mouse model study [J].

Santos, Andre A., Jr. ;

Rodrigues-Junior, Valnes ;

Zanin, Rafael F. ;

Borges, Thiago J. ;

Bonorino, Cristina ;

Coutinho-Silva, Robson ;

Takyia, Christina M. ;

Santos, Diogenes S. ;

Campos, Maria M. ;

Morrone, Fernanda B. .

IMMUNOBIOLOGY, 2013, 218 (08) :1104-1112

[10]

Vasconcelos I. B., 2008, Anti-Infective Agents in Medicinal Chemistry, V7, P50

← 1 2 →