pncA Mutations as a Major Mechanism of Pyrazinamide Resistance in Mycobacterium tuberculosis : Spread of a Monoresistant Strain in Quebec, Canada

Author:

Cheng Shao-Ji1,Thibert Louise2,Sanchez Tracy3,Heifets Leonid3,Zhang Ying1

Affiliation:

1. Department of Molecular Microbiology and Immunology, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Maryland 212051;

2. Laboratoire de Sante Publique du Quebec, Sainte-Anne-de-Bellevue, Canada2; and

3. National Jewish Medical and Research Center, Denver, Colorado 802063

Abstract

ABSTRACT Pyrazinamide (PZA) is an important first-line tuberculosis drug that is part of the currently used short-course tuberculosis chemotherapy. PZA is a prodrug that has to be converted to the active form pyrazinoic acid by pyrazinamidase (PZase) activity, encoded by the pncA gene of Mycobacterium tuberculosis , and loss of PZase activity is associated with PZA resistance. To further define the genetic basis of PZA resistance and determine the frequency of PZA-resistant strains having pncA mutations, we sequenced the pncA gene from a panel of 59 PZA-resistant clinical isolates from Canada, the United States, and Korea. Two strains that did not contain pncA mutations and had positive PZase turned out to be falsely resistant. Three PZase-negative strains (MIC, >900 μg of PZA per ml) and one PZase-positive strain (strain 9739) (MIC, >300 μg of PZA per ml) did not have pncA mutations. The remaining 53 of the 57 PZA-resistant isolates had pncA mutations, confirming that pncA mutation is the major mechanism of PZA resistance. Various new and diverse mutations were found in the pncA gene. Interestingly, 20 PZA-monoresistant strains and 1 multidrug-resistant isolate from Quebec, Canada, all had the same pncA mutation profile, consisting of an 8-nucleotide deletion and an amino acid substitution of Arg140→Ser. Strain typing indicated that these strains are highly related and share almost identical IS 6110 patterns. These data strongly suggest the spread of a PZA-monoresistant strain, which has not previously been described.

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology

Reference24 articles.

1. Heifets L. B. Drug susceptibility tests in the management of chemotherapy of tuberculosis Drug susceptibility in the chemotherapy of mycobacterial infections. Heifets L. B. 1991 89 122 CRC Press Boca Raton Fla

2. Heifets L. B. Pyrazinamide Antimicrobial therapy and vaccines. Yu V. L. Merigan T. C. Barriere S. L. 1999 668 676 Williams and Wilkins Baltimore Md

3. Drug-resistant tuberculosis: inconsistent results of pyrazinamide susceptibility testing.;Hewlett D.;JAMA,1995

4. Mutation in pncA is a major mechanism of pyrazinamide resistance in Mycobacterium tuberculosis.;Hirano K.;Tuber. Lung Dis.,1997

5. Pyrazinamide susceptibility and amidase activity of tubercle bacilli.;Konno K.;Am. Rev. Respir. Dis.,1967

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3