M TUBERCULOSIS ADENOSINE KINASE AND ANTI-MICROBIAL NUCLEOSIDE ANALOGS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Mycobacterium tuberculosis is an opportunistic infection pathogen that causes TB and morbidity and mortality worldwide. The emergence of multi-drug resistance (MDR) strains and the AIDS-associated TB infection has led to a critical need for the development of new and effective therapeutic agents for the TB treatment. Adenosine kinase from M. tuberculosis (Mtb-AK) has recently been identified to be responsible for the bioactivation of a group of nucleoside analogs against M. tuberculosis. Our long-term goal is to develop new antimycobacterial agents by exploiting the specific activation of a nucleoside prodrug by Mtb-AK, a key enzyme in the purine salvage pathway. Our specific aims are: 1). to characterize the crystal structure of Mtb-AK in different forms and to elute the enzyme reaction mechanism involved in adenosine phosphorylation and bioactivation of adenosine analogs in M. tuberculosis. 2) To characterize the structural basis of the enzyme's substrate preferences and the structural features of nucleoside analogs that can be activated more efficiently and selectively by Mtb-AK. 3) To characterize the Mtb-AK complex structures with the lead adenosine analogs and the structural basis for optimization of nucleoside analogs.