tuberculosis have been synthesized (Lilienkampf

et al, 2

tuberculosis have been synthesized (Lilienkampf

et al., 2009; Upadhayaya et al., 2009). Diarylquinolines were also shown to kill dormant M. tuberculosis as effectively as replicating bacilli and to inhibit ATP synthesis in dormant M. smegmatis (Koul et al., 2008). This unique dual bactericidal activity, with equal potency on replicating and dormant bacilli, distinguishes diarylquinolines from all the currently used antituberculosis drugs, such as isoniazid and rifampicin. CP 868596 These front-line drugs show significantly less activity on dormant mycobacteria as compared with replicating bacilli (Koul et al., 2008; Rao et al., 2008). Thus, although ATP synthase is significantly downregulated during dormancy, its residual activity Enzalutamide supplier appears to be essential for mycobacteria irrespective of their

physiological state. This makes ATP synthase an efficient drug target to tackle both replicating as well as dormant bacilli. In vivo experiments using mouse models indicated that diarylquinolines have bactericidal activity exceeding the effect of current first-line antibiotics (Andries et al., 2005; Lounis et al., 2006). Diarylquinolines, in particular when applied in combination therapy with the first-line antibiotic pyrazinamide, have a strong potential for shortening the duration of tuberculosis treatment (Lounis et al., 2006; Ibrahim et al., 2007). The physiological basis for this observed synergy remains obscure. In phase IIb clinical tests, the addition of TMC207 to standard therapy strongly decreased the count of CFU in the sputum of patients with multi-drug-resistant tuberculosis as compared find more with an active-placebo group (Diacon et al., 2009). TMC207 also accelerated conversion to a negative sputum culture, as compared with a placebo. These findings validate ATP synthase as a target for the treatment of tuberculosis. Respiratory ATP production is not only essential for growth, but also represents a critical weak point in dormant mycobacteria. Although most enzymes involved in respiratory

ATP synthesis are conserved between prokaryotes and eukaryotes, targeting ATP production may be a highly efficient approach for the development of antibacterial drugs. The strategy may be to target enzymes, which do not have homologs in human metabolism, as in the case of NDH-2. Alternatively, as applied for ATP synthase, small differences in the structure between a bacterial enzyme and a human homologue may be utilized for selective inhibition. Understanding respiratory ATP production in replicating and dormant mycobacteria will not only fuel development of novel drugs but also shed light on how these bacteria perform their intriguing task of extreme persistence without significant growth. The authors wish to thank Prof. Dr H. Lill (VU Amsterdam) and Prof. Dr K. Andries (Johnson and Johnson) for critically reading the manuscript, and Dr J. Guillemont, Dr E.

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