Recent statistics lists tuberculosis (TB) as a serious infectious disease that kills nearly 2 million people worldwide each year. 1/3rd of the world's population is infected with the bacterial pathogen, M. tuberculosis (Mtb) that causes TB. HIV/AIDs increases the risk of getting TB and multi-drug resistant (MDR) Mtb strains are on the rise, threatening the world population. Treatment of TB requires multiple drugs delivered concurrently for at least 6 months. Failure to provide adequate drugs or to complete the long term therapy results in emergency of MDR Mtb. In order to control the current TB epidemic and finally eradicate the disease, new potent drugs that can shorten the treatment active disease and eliminate latently infected Mtb from asymptomatic patients are desperately needed. Since its founding in 1997, Sequella Inc. has been contributing its entire R&D efforts in the development of new tools for TB, including new drugs. Centered on the company's mission, this application describes the research plans for the development of a novel class of Mtb translocase I inhibitors that block the biosynthesis of peptidoglycan in the bacterial cell wall. The goal is to identify the best inhibitors in the class and to complete the pharmacological characterization of the compounds required for advancing 1 or more into preclinical phase of the development. 3 candidates (1 is a natural compound) initially discovered and studied at Sankyo Pharma Inc. inhibit Mtb growth in cultures and in infected mice, have low cytotoxicity, are active against MDR-Mtb, and show high tissue distribution in lungs. To continue the R&D of these compounds, we plan to evaluate their in vivo efficacy in mouse models of TB emphasizing on oral activity. We will explore pharmacophore diversity of the natural compound by chemical modification. The new derivatives will be filtered throughout a series of screens for ability to inhibit translocase I activity, inhibition of Mtb growth in culture (MIC determination), toxicity in human cells using MTS assay, and in vivo activity using a rapid mouse model of TB. The top hits selected from the original 3 and the new hits will be evaluated further for in vivo efficacy in a chronic mouse model of TB, in which the ability of each drug candidate to kill or inhibit Mtb replication in mouse lung and spleen of infected animals is determined directly by colony-forming units. This phase I proposal will allow us to select the most active anti-Mtb translocase I inhibitors that can be advanced to the next phase of drug development. ? ? ?
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