GENETIC ANALYSIS OF MYCOLIC ACID SYNTHESIS

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The unique architecture of the mycobacterial cell wall is due to the novel arrangement of the covalently bound mycolic acids and the characteristic arabinogalactan-peptidoglycan complex. Undoubtedly, the biosynthetic pathways for the biosynthesis of this cell wall matrix will involve highly specialized enzymes and enzyme complexes that may be exploited for the development of new anti-mycobacterial drugs. The urgent need to develop new and more effective chemotherapeutic agents to control tuberculosis has lead to our current endeavors in defining the biosynthesis of key cell wall products. Among the most distinctive targets for rational drug design against tuberculosis and atypical mycobacterioses are the cell wall mycolates - alpha-alkyl, beta-hydroxy long chain (C80) fatty acids. The study of their biosynthesis, presumably involving specialized elongation, Claisen condensation and "transporters; (Project 1), will be complemented by identification of genes, generation of isogeneic mutants, and provision of recombinant enzymes for SAR studies. With our key observation that a primary mycolyltransferase is the well known antigen 85, alpha-antigen complex, the genes encoding a key target are thus known and are ripe for construction of "knock-out" mutants. The recent availability of FAS-I and -II enzymes, allows for their genes to be located by reverse genetics and also manipulated. Already recombinant M. tuberculosis mycolates have been expressed in M. smegmatis providing a ready means for genetic definition f the most characteristic phenotype of the tubercle bacillus, and also the site of effective drugs, and, in the eyes of our industrial partners, a prime focus for new drug development.