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

With the completion of the genome of Mycobacterium tuberculosis comes the p romise of a new generation of potent drugs to combat the emerging epidemic of multiply drug-resistant isolates. Translating this genomic information i nto realistic assays, valid targets, and preclinical drug candidates repres ents 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 DN A microarrays coupled with the emerging discipline of combinatorial chemist ry. A comparison of currently used antituberculars with the properties of o ther pharmaceuticals suggests that such compounds will have a defined range of physiochemical properties. In general, we can expect the next generatio n of antituberculars to be small, relatively hydrophilic molecules that bin d tightly to specific cellular targets. Many current antimycobacterials req uire 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 activ ation of current antimycobacterial therapeutics also may facilitate the dev elopment of alternative activation strategies or of analogs that require no such processes. (C) 1999 Elsevier Science Inc.