The bicyclic
nitroimidazole-like molecule
PA-824 has activity both against replicating and hypoxic non-replicating Mycobacterium tuberculosis, raising the possibility that it may have a role in the treatment of
latent tuberculosis infection (LTBI). This study aimed to examine the bactericidal and sterilising activities of
PA-824 against LTBI in C3HeB/FeJ mice, which develop hypoxic, necrotic
granulomas histologically resembling their human counterparts. Female 5-6-week-old C3HeB/FeJ mice were immunised via the
aerosol route with a recombinant BCG strain overexpressing the 30-kDa major secretory
protein (rBCG30) and were
aerosol-infected 6 weeks later with virulent M.
tuberculosis H37Rv. Six weeks after M.
tuberculosis infection, separate groups of mice were left untreated (negative controls) or were treated with either
rifampicin,
isoniazid (INH) or
PA-824. Culture-positive relapse was assessed in subgroups of mice after 2 months and 4 months of treatment. Human-equivalent doses of
PA-824 given five times weekly showed similar bactericidal activity as INH at Months 1, 2 and 4 of treatment, and 15/15 mice treated with either
PA-824 or INH showed lung-culture relapse 3 months after completion of treatment. To the best of our knowledge, this is the first report examining the sterilising activity of
PA-824 in an animal model of LTBI. This model may be useful for screening the efficacy of novel drugs against LTBI, particularly those with specific activity against bacilli residing within necrotic lung
granulomas.