Mycobacterium tuberculosis and related pathogenic mycobacteria have large amounts of unique lipids in their cell walls. Some of these unique lipids are surface antigens of the pathogenic mycobacteria and can be useful in identification, diagnosis and treatment. These lipids constitute barriers that allow the bacteria to resist the natural defenses of the host, resist antimicrobial drugs and help multiply within the host. The antimycobacterial drugs currently in use are directed against the biosynthesis of mycolic acids, one class of the unique lipids. Resistance against these drugs has become a major problem. Biosynthesis of other unique lipids could be suitable targets for new antimycobacterial drugs. Multiple methyl branched very long chain fatty acids such as mycocerosic acids and the beta-diols, phthiocerol and phenolphthiocerol, to which these acids are esterified, are unique constituents of the cell wall lipids of the slow growing pathogenic mycobacteria. Even the fatty acid synthase of mycobacteria has the unique ability to catalyze both de novo synthesis of fatty acids and chain elongation to generate the very long chain acid precursors of the unique mycobacterial lipids. Understanding of the biochemistry and molecular biology of these unique lipids could help design new drugs. To this end, we propose to pursue the following specific objectives: 1. Determine how mycocerosic acids are channeled from mycocerosic acid synthase to phthiocerol and phenolthiocerol in the cell wall structure. 2. Disrupt the mycocerosic acid synthase gene and determine the consequences on the cell wall structure susceptibility and virulence. 3. Determine the domains in mycocerosic acid synthase responsible for the selective incorporation of methylmalonyl-CoA to generate the multiple methyl branched cell wall lipids. 4. Elucidate the pathway, enzymology and structure of the gene involved in the biosynthesis of phthiocerol and phenolphthiocerol. 5. Elucidate the structural relationship between mycocerosic acid synthase and the fatty acid synthase and elucidate the molecular basis of the unique capability of mycobacterial fatty acid synthase to catalyze both de novo fatty acid synthesis and chain elongation. It is possible that the proposed elucidation of unique processes in pathogenic mycobacteria could lead to novel methods to identify and diagnose mycobacterial infections that kill millions of people annually and to combat the resurgence of tuberculosis and other mycobacterial infections in AIDS patients in the United States.
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