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Chemotherapeutic options to treat tuberculosis are severely restricted by the intrinsic resistance of Mycobacterium tuberculosis to the majority of clinically applied antibiotics. Such resistance is partially provided by the low permeability of their unique cell envelope. Here we describe a complementary system that coordinates resistance to drugs that have penetrated the envelope, allowing mycobacteria to tolerate diverse classes of antibiotics that inhibit cytoplasmic targets. This system depends on whiB7, a gene that pathogenic Mycobacterium shares with Streptomyces, a phylogenetically related genus known as the source of diverse antibiotics. In M. tuberculosis, whiB7 is induced by subinhibitory concentrations of antibiotics (erythromycin, tetracycline, and streptomycin) and whiB7 null mutants (Streptomyces and Mycobacterium) are hypersusceptible to antibiotics in vitro. M. tuberculosis is also antibiotic sensitive within a monocyte model system. In addition to antibiotics, whiB7 is induced by exposure to fatty acids that pathogenic Mycobacterium species may accumulate internally or encounter within eukaryotic hosts during infection. Gene expression profiling analyses demonstrate that whiB7 transcription determines drug resistance by activating expression of a regulon including genes involved in ribosomal protection and antibiotic efflux. Components of the whiB7 system may serve as attractive targets for the identification of inhibitors that render 114. tuberculosis or multidrug-resistant derivatives more antibiotic-sensitive. multidrug resistance | Streptornyces | WhiB | microarray | gene expression

The antibiotic clarithromycin seems to be effective in preventing Mycobacterium avium complex infections in AIDS patients. Of 677 AIDS patients with no history of this opportunistic infection, 333 began taking clarithromycin and 334 began taking a placebo. Only 19 (6%) of those taking clarithromycin developed the infection, compared to 53 (16%) of those taking placebo. Clarithromycin reduced the mortality rate by 25% during the 10-month follow-up. Eleven of the 19 patients taking clarithromycin who developed the infection had a drug-resistant strain.

Abstract Background Latent tuberculosis infection (LTBI) is affecting one-third of the world population, and activation of LTBI is a substantial source of new cases of tuberculosis. LTBI is caused by tubercle bacilli in a state of non-replicating persistence (NRP), and the goal of this study was to evaluate the activity in vitro of various antimicrobial agents against non-replicating M. tuberculosis. Methods To achieve a state of NRP we placed broth cultures of M. tuberculosis (three strains) in anaerobic conditions, and in this model tested all known anti-TB drugs and some other antimicrobial agents (a total of 32 drugs). The potential effect was evaluated by plating samples from broth cultures for determining the number of viable bacteria (CFU/ml) during a prolonged period of cultivation. Besides drug-free controls we used metronidazole for positive controls, the only drug known so far to be effective against tubercle bacilli in anaerobic setting. Results On a background of non-replicating conditions in drug-free cultures and clear bactericidal effect of metronidazole none of the antimicrobial agents tested produced effect similar to that of metronidazole except capreomycin, which was as bactericidal at the same level as metronidazole. Conclusion The unique ability of capreomycin to be bactericidal in vitro among the anti-TB drugs against non-replicating tubercle bacilli may justify the search for other drugs among peptide antibiotics with similar activity. This phenomenon requires further studies on the mechanism of action of capreomycin, and evaluation of its activity in appropriate animal models.