title: Metronidazole lacks activity against Mycobacterium tuberculosis in an in vivo hypoxic granuloma model of latency.
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.
authors.affiliation: Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231-1001, USA.
authors.forename: Lee G
authors.initials: LG
authors.lastname: Klinkenberg
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Sutherland
authors.forename: William R
authors.initials: WR
authors.lastname: Bishai
authors.forename: Petros C
authors.initials: PC
authors.lastname: Karakousis
mesh_terms: D000336:Aerosols; D000818:Animals; D000890:Anti-Infective Agents / Q000627:therapeutic use*; D015687:Cell Hypoxia / Q000502:physiology*; D004251:DNA Transposable Elements; D004195:Disease Models, Animal; D024881:Drug Resistance, Bacterial; D005260:Female; D006099:Granuloma / Q000382:microbiology*; D006168:Guinea Pigs; D008795:Metronidazole / Q000627:therapeutic use*; D051379:Mice; D008812:Mice, Hairless; D016296:Mutagenesis; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D017211:Treatment Failure
chemical_list: D000336:Aerosols; D000890:Anti-Infective Agents; D004251:DNA Transposable Elements; D008795:Metronidazole