Metronidazole lacks activity against Mycobacterium tuberculosis in an in vivo hypoxic granuloma model of latency

Lee G. Klinkenberg, Lesley A. Sutherland, William R. Bishai, Petros C. Karakousis

Research output: Contribution to journalArticlepeer-review

Abstract

During human latent tuberculosis (TB) infection, dormant bacilli putatively reside within the hypoxic environment of caseating lung granulomas. The anaerobic drug metronidazole has antituberculous activity under hypoxic conditions in vitro but lacks activity against murine TB. In the present study, we used the hypoxia marker pimonidazole to demonstrate the presence of hypoxia in a novel in vivo granuloma model of Mycobacterium tuberculosis latency. We also used a high-throughput, microarray-based technique to identify mycobacterial genes essential to hypoxia and showed that this in vivo model correctly identified 51% of hypoxia-attenuated mutants, a significantly larger percentage than that identified by the mouse (29%) and guinea pig (29%) aerosol models of TB. Although isoniazid showed activity during the first 28 days of therapy and rifampin was active against dormant bacilli after the establishment of hypoxia, metronidazole showed no antituberculous activity in this in vivo hypoxic granuloma model of M. tuberculosis dormancy.

Original languageEnglish (US)
Pages (from-to)275-283
Number of pages9
JournalJournal of Infectious Diseases
Volume198
Issue number2
DOIs
StatePublished - Jul 15 2008

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

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