? Drug-resistant tuberculosis now threatens a large portion of the earth's population, and the development of new treatments for tuberculosis infection has become a national and international priority. Mycobacterium tuberculosis depends on a low molecular weight thiol, """"""""mycothiol,"""""""" to maintain a reducing intracellular environment and to remove exogenous electrophilic agents. Disruption of the enzymatic pathways of mycothiol biosynthesis and/or mycothiol-based detoxification could leave M. tuberculosis vulnerable to drugs, oxygen, and other stress factors, and constitutes a new tactic for the control of tuberculosis. The objective of this project is to develop inhibitors of the mycothiol-related enzymes of M. tuberculosis, and eventually to design new and successful treatments for tuberculosis. Three enzymes will be targeted initially: mycothione reductase, mycothiol S-conjugate amidase, and inosityl GIcNAc deacetylase, although others, including a cysteine ligase and a cysteine transacetylase, could be added. This work will be guided by enzymatic assays conducted by collaborators using existing screens, and by preliminary results that already indicate that substantial structural simplification in designing mycothiol analogues is possible. First, the minimum substrate requirements for the M. tuberculosis enzymes will be defined. Then, inhibitors based on these minimum structures will be synthesized and evaluated. New methods for the synthesis of mycothiol-analogous compounds will be developed, and new ideas for enzyme inhibitor design will be explored. The most active compounds will be taken as leads for further analogue development and for increasing the potency, specificity, bioavailability, and metabolic stability in M. tuberculosis itself. ? ?
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