title: Pyrazinamide resistance in Mycobacterium tuberculosis: Review and update.
abstract: The global control and management of tuberculosis (TB) is faced with the formidable challenge of worsening scenarios of drug-resistant disease. Pyrazinamide (PZA) is an indispensable first-line drug used for the treatment of TB. It plays a key role in reducing TB relapse rates, shortening the course of the disease treatment from 9-12 months to 6 months, and the treatment of patients infected with bacillary strains that are resistant to at least isoniazid and rifampicin. Additionally, it is the only first-line anti-TB drug most likely to be maintained in all new regimens, which are aimed at reducing the treatment period of susceptible, multi-drug resistant and extensively drug-resistant TB. It has a preferential sterilizing activity against non-replicating persister bacilli with low metabolism at acid pH in vitro or in vivo during active inflammation where other drugs may not act so well. PZA seem to have a non-specific cellular target and instead, exerts its anti-mycobacterial effect by disrupting the membrane energetics, the trans-translation process, acidification of the cytoplasm and perhaps coenzyme A synthesis, which is required for survival of Mycobacterium tuberculosis (MTB) persisters. Indeed, the emergence of MTB strains resistant to PZA represents an important clinical and public health problem. The essential role of PZA in TB treatment underlines the need for accurate and rapid detection of its resistance. This article presents an updated review of the molecular mechanisms of drug action and resistance in MTB against PZA, commenting on the several research gaps and proposed drug targets for PZA.
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
authors.forename: Moses
authors.initials: M
authors.lastname: Njire
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Chest Hospital, Guangzhou, China.
authors.forename: Yaoju
authors.initials: Y
authors.lastname: Tan
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
authors.forename: Julius
authors.initials: J
authors.lastname: Mugweru
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
authors.forename: Changwei
authors.initials: C
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
authors.forename: Jintao
authors.initials: J
authors.lastname: Guo
authors.affiliation: Stanley Ho Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: WingWai
authors.initials: W
authors.lastname: Yew
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Chest Hospital, Guangzhou, China. Electronic address: tanshyo@tom.com.
authors.forename: Shouyong
authors.initials: S
authors.lastname: Tan
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China. Electronic address: zhang_tianyu@gibh.ac.cn.
authors.forename: Tianyu
authors.initials: T
authors.lastname: Zhang
mesh_terms: D000818:Animals; D024881:Drug Resistance, Bacterial / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008826:Microbial Sensitivity Tests; D009154:Mutation / Q000235:genetics; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D011718:Pyrazinamide / Q000737:chemistry / Q000494:pharmacology*; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology
chemical_list: D011718:Pyrazinamide
keywords: Drug resistance; MDR; Pyrazinamide; Tuberculosis; XDR