Structural and functional studies of mycolic acid synthesis in Mycobacterium tuberculosis

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Despite the containment of tuberculosis (TB) in the developed world through antibiotics, it remains a public health problem of global proportion. The problem is made worse by emerging strains of the tubercle bacillus (Mycobacterium tuberculosis) that have become resistant against one or several of today's antitubercular drugs. New and more effective treatment options are urgently needed to control TB. Since the time of Koch, M. tuberculosis and related organisms have been known for the thick, waxy envelope surrounding the bacterium. This cell envelope comprises lipid, polysaccharide and peptide components in a highly organised layered structure. We understand in part, how these components are made and assembled by the bacillus, but the understanding is incomplete in many respects. This proposal focuses on a component of the cell envelope called mycolic acids, which make up to 10% of the biomass of the tubercle bacillus and are essential for survival. Mycolic acids are a particular kind of fatty acids that comprise a characteristic long arm, the meromycolate chain, and a shorter arm, the alfa-alkyl chain. We are interested in clarifying the 3-dimensional atomic structures of several enzymes that form a part of the catalytic assembly line making mycolic acids. We are also interested to learn how these enzymes work with other components of the assembly line, and how this is regulated. We employ X-ray crystallography and a range of other experimental techniques, to give us details of the molecular structure of the enzymes in question, and of interactions taking place between them. Such information will provide a more complete understanding of mycolic acid synthesis and may, in the long term, aid the process of finding new therapeutics against this ancient adversary of humanity.