? This Proposal is in response to PA-01-113, """"""""Therapeutics Research on AIDS-Associated Opportunistic Infections and Malignancies"""""""" and specifically addresses the study of Mycobacterium tuberculosis (MTB). The thrust of this proposal is the development of novel drug targets to counteract multiple drug resistant organisms. The long-term goal of this research program is to develop novel classes of chemotherapeutics that target the regulation, and coordination of chromosomal segregation and cellular division in MTB. Toward this objective we have identified in the MTB genome, gene products that are homologous to proteins associated with these processes in other prokaryotes. Moreover, our preliminary results provide strong evidence that some of these gene products (FtsZ and Ftsl homologues) actively participate in the cellular division of MTB. However, a more extensive analysis of these gene products and global assessment of the potential regulatory networks involved in the division of MTB cells are required. Similar to work with Caulobacter crescentus we hypothesize that DNA microarray analysis with synchronized cultures of MTB will allow us to develop a detailed pattern of gene expression profiles across the entire cell division cycle of this bacterium. Additionally, the use of known inhibitors of early (FtsZ activity) and late (Ftsl activity) events of cell division along with global gene expression studies will further elucidate the regulatory networks that are activated during different stages of cell division. A final analysis of putative regulatory genes already identified and new ones elucidated through gene expression profiling will enable us to develop a detailed picture of the regulatory networks and temporal gene expression responsible for MTB cellular division. Such studies will ensure that future resources are well directed at appropriate chemotherapeutic targets and developing suitable drug discovery strategies. Thus, the studies proposed in this application are designed to examine the replication dynamics of MTB, specifically focusing on cell cycle-regulated genes that are involved in cell division. ? ? ?
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