Pharmacological and Molecular Mechanisms Behind the Sterilizing Activity of Pyrazinamide

被引：41

作者：

Gopal, Pooja ^{[1
,6
]}

Gruber, Gerhard ^{[2
]}

Dartois, Ronique ^{[3
,4
]}

Dick, Thomas ^{[3
,4
,5
]}

机构：

[1] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, 14 Med Dr, Singapore 117599, Singapore

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

[3] Hackensack Meridian Hlth, Ctr Discovery & Innovat, 340 Kingsland St,Bldg 102, Hackensack, NJ 07110 USA

[4] Seton Hall Univ, Dept Med Sci, Hackensack Meridian Sch Med, 340 Kingsland St, Nutley, NJ 07110 USA

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

[6] Merck Res Labs, MSD Translat Med Res Ctr, 8 Biomed Grove, Singapore 138665, Singapore

来源：

TRENDS IN PHARMACOLOGICAL SCIENCES | 2019年 / 40卷 / 12期

基金：

美国国家卫生研究院; 英国医学研究理事会;

关键词：

MYCOBACTERIUM-TUBERCULOSIS; PYRAZINOIC ACID; ANTITUBERCULOSIS DRUGS; NEUTRAL PH; RESISTANCE; PNCA; PANTOTHENATE; MUTATIONS; MURINE; SUSCEPTIBILITY;

D O I：

10.1016/j.tips.2019.10.005

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Inclusion of pyrazinamide (PZA) in the tuberculosis (TB) drug regimen during the 1970s enabled a reduction in treatment duration from 12 to 6 months. PZA has this remarkable effect in patients despite displaying poor potency against Mycobacterium tuberculosis (Mtb) in vitro. The pharma-cologicalbasis for the in vivo sterilizing activity of the drug has remained obscure and its bacterial target controversial. Recently it was shown that PZA penetrates necrotic caseous TB lung lesions and kills nongrowing, drug-tolerant bacilli. Furthermore, it was uncovered that PZA inhibits bacterial Coenzyme A biosynthesis. It may block this pathway by triggering degradation of its target, aspartate decarboxylase. The elucidation of the pharmacological and molecular mechanisms of PZA provides the basis for the rational discovery of the next-generation PZA with improved in vitro potency while maintaining attractive pharmacological properties.

引用

页码：930 / 940

页数：11

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