Analysis of the phthiocerol dimycocerosate locus of Mycobacterium tuberculosis - Evidence that this lipid is involved in the cell wall permeability barrier

Among the few characterized genes that have products involved in the pathog enicity of Mycobacterium tuberculosis, the etiological agent of tuberculosi s, are those of the phthiocerol dimycocerosate (DIM) locus. Genes involved in biosynthesis of these compounds are grouped on a 50-kilobase fragment of the chromosome containing 13 genes. Analysis of mRNA produced from this 50 -kilobase fragment in the wild type strain showed that this region is subdi vided into three transcriptional units. Biochemical characterization of fiv e mutants with transposon insertions in this region demonstrated that (i) t he complete DIM molecules are synthesized in the cytoplasm of M. tuberculos is before being translocated into the cell wall; (ii) the genes fadD26 and fadD28 are directly involved in their biosynthesis; and (iii) both the drrC and mmpL7 genes are necessary for the proper localization of DIMs. Inserti onal mutants unable to synthesize or translocate DIMs exhibit higher cell. wall permeability and are more sensitive to detergent than the wild type st rain, indicating for the first time that, in addition to being important vi rulence factors, extractable lipids of M. tuberculosis play a role in the c ell envelope architecture and permeability. This function may represent one of the molecular mechanisms by which DIMs are involved in the virulence of M. tuberculosis.