Use of genomics and combinatorial chemistry in the development of new antimycobacterial drugs.

With the completion of the genome of Mycobacterium tuberculosis comes the promise of a new generation of potent drugs to combat the emerging epidemic of multiply drug-resistant isolates. Translating this genomic information into realistic assays, valid targets, and preclinical drug candidates represents the next great hope in tuberculosis control. We propose a paradigm for exploiting the genome to inform the development of novel antituberculars, utilizing the techniques of differential gene expression as monitored by DNA microarrays coupled with the emerging discipline of combinatorial chemistry. A comparison of currently used antituberculars with the properties of other pharmaceuticals suggests that such compounds will have a defined range of physiochemical properties. In general, we can expect the next generation of antituberculars to be small, relatively hydrophilic molecules that bind tightly to specific cellular targets. Many current antimycobacterials require some form of cellular activation (e.g. the activation of isoniazid by a catalase-peroxidase). Activation corresponds to the oxidative, reductive, or hydrolytic unmasking of reactive groups, which occurs with many current antimycobacterial prodrugs. Understanding the mechanisms involved in activation of current antimycobacterial therapeutics also may facilitate the development of alternative activation strategies or of analogs that require no such processes.