Mycobacterium tuberculosis has proven to be a challenging target for drug discovery, with no new anti-tubercular drugs identified in decades. With the rise in multidrug-resistant TB, new therapeutic agents are urgently needed. In the 14 January 2005 issue of Science, Andries et al. report the identification of a new class of drugs, diarylquinolines, that target the mycobacterial ATP synthase.
Based on whole cell assays, the authors identified diarylquinolines as a new class of small molecules that inhibit the growth of Mycobacterium smegmatis. After chemical optimization, the most active inhibitor, R207910, had bactericidal activity against Mycobacterium tuberculosis exceeding the main anti-TB drugs, rifampin and isoniazid.
Diarylquinolines are related to the existing quinolone class of antibiotics, but are structurally distinct, suggesting a different mode of action. To identify the drug target, the authors selected for R207910 resistant strains of multiple mycobacterial species. None had mutations in DNA gyrase genes, where quinolone resistance is typically found. Through whole genome sequencing, they identified point mutations in atpE, part of the F0 subunit of ATP synthase, in each resistant strain. Introduction of the atpE mutant into wild-type M. smegmatis resulted in R207910 resistance, confirming that R207910 targets the ATP synthase.
Initial studies suggest that the serum levels of R207910 necessary for in vivo activity in mice, are well-tolerated in humans. R207910 is currently under clinical development and may provide a new weapon for combating drug-resistant TB.
