TY - JOUR
T1 - Metronidazole lacks activity against Mycobacterium tuberculosis in an in vivo hypoxic granuloma model of latency
AU - Klinkenberg, Lee G.
AU - Sutherland, Lesley A.
AU - Bishai, William R.
AU - Karakousis, Petros C.
N1 - Funding Information:
Financial support: National Institutes of Health (grants AI043846, AI37856, AI36973, and AI007608 and contract AI30036 to W.R.B., and grant AI064229 to P.C.K.); Potts Memorial Foundation (fellowship to L.G.K.).
PY - 2008/7/15
Y1 - 2008/7/15
N2 - 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.
AB - 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.
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U2 - 10.1086/589515
DO - 10.1086/589515
M3 - Article
C2 - 18491971
AN - SCOPUS:47649096186
SN - 0022-1899
VL - 198
SP - 275
EP - 283
JO - Journal of Infectious Diseases
JF - Journal of Infectious Diseases
IS - 2
ER -