MYCOBACTERIUM-BOVIS BCG GENES INVOLVED IN THE BIOSYNTHESIS OF CYCLOPROPYL KETOMOCOLIC AND HYDROXYMYCOLIC ACIDS

The resurgence of tuberculosis and the emergence of multidrug-resistan t mycobacteria necessitate the development of new antituberculosis dru gs. The biosynthesis of mycolic acids, essential elements of the mycob acterial envelope, is a good target for chemotherapy. Species of the M ycobacterium tuberculosis complex synthesize oxygenated mycolic acids with keto and methoxy functions. In contrast, the fast-growing Mycobac terium smegmatis synthesizes oxygenated mycolic acids with an epoxy fu nction. We describe the isolation and sequencing of a cluster of four genes from Mycobacterium bovis bacillus Calmette-Guerin (BCG), coding for methyl transferases, and which, when transferred into M. smegmatis , allow the synthesis of ketomycolic acid, in addition to an as yet un described mycolic acid, hydroxymycolic acid. These oxygenated mycolic acids, unlike the regular mycolic acids of M. smegmatis, and similar t o the mycolic acids of M. bovis, are highly cyclopropanated. Furthermo re, there is a perfect match between the structures of the keto- and t he hydroxy-mycolic acids. We propose a biosynthetic model in which the re is a direct relationship between these two types of mycolic acid.