Core The objective of this PO-1, 'MDR-TB Drugs: Targeting Cell Wall Synthetic Enzymes', is to identify several lead compounds of various structures that can effectively kill M. tuberculosis in lungs, without toxic or pathologic effects, under different mouse model conditions. Compounds are synthesized under a Compound Development Module and analyzed by a Compound Analysis Module. The Analysis Module includes the determination of enzyme inhibition, MIC values against MDR-TB, and ultimately, activity in mice. The latter will be carried out under this Core, titled 'Early preclinical testing of TB drugs in mice'. Data will be communicated to the Compound Development Module for further compound refinement. In this Core, we propose to provide our extensive Biosafety Level III facilities at CSU, combined with our recognized expertise in small animal in vivo models of tuberculosis infection, to evaluate compounds in early preclinical phase against M. tuberculosis. Compounds found active in enzyme based assays and in vitro assays will be tested for their capacity to inhibit the growth of virulent Mycobacterium tuberculosis in lungs of C57BL/6 mice exposed to low dose aerosol infection with this organism. In addition, we will provide extensive toxicology and histopathology assessments, as well as basic pharmacology. For the evaluation of the compounds in vivo, a sequence of testing procedures will be followed: initial toxicity testing of the compound to ensure safe use in mice, followed by testing of the efficacy in a rapid tuberculosis infection mouse model and finally evaluation of the compound in a standard TB infection mouse model.
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