Maximizing bactericidal activity with combinations of bioreduced drugs.

Certain antimicrobial and anticancer drugs are only active following bioactivation within the target cell. Nitroimidazoles, nitrofurans and quinoxaline-di-N-oxides represent three chemical classes that are active as anti-tubercular drugs following intracellular bioreduction to reactive intermediates. Two nitroimidazoles are in clinical trials as new anti-tubercular drugs with significant bactericidal activity as well as activity on nonreplicating bacteria. Nitrofurans and quinoxaline-di-N-oxides, which are in preclinical development, also exhibit bactericidal activity and activity on nonreplicating bacteria. Current data indicate these drugs are bioreduced via distinct pathways that yield reactive free radical species. Since flux though each system would become saturated due to enzyme kinetics, cellular uptake or maximum drug concentration attainable in the host, one may propose that using three distinct systems simultaneously could produce a larger burst of free radicals to rapidly and efficiently kill bacteria and shorten the time to cure for tuberculosis. Arguments for the possible development of a novel combination therapy with maximized bacterial cell killing and the possibility of shortening the time to cure will be presented.