Mycolic acids: structures, biosynthesis, and beyond.

Mycolic acids are major and specific lipid components of the mycobacterial cell envelope and are essential for the survival of members of the genus Mycobacterium that contains the causative agents of both tuberculosis and leprosy. In the alarming context of the emergence of multidrug-resistant, extremely drug-resistant, and totally drug-resistant tuberculosis, understanding the biosynthesis of these critical determinants of the mycobacterial physiology is an important goal to achieve, because it may open an avenue for the development of novel antimycobacterial agents. This review focuses on the chemistry, structures, and known inhibitors of mycolic acids and describes progress in deciphering the mycolic acid biosynthetic pathway. The functional and key biological roles of these molecules are also discussed, providing a historical perspective in this dynamic area.

Lepromatous leprosy patients produce antibodies that recognise non-bilayer lipid arrangements containing mycolic acids

Non-bilayer phospholipid arrangements are three-dimensional structures that form when anionic phospholipids with an intermediate structure of the tubular hexagonal phase II are present in a bilayer of lipids. Antibodies that recognise these arrangements have been described in patients with antiphospholipid syndrome and/or systemic lupus erythematosus and in those with preeclampsia; these antibodies have also been documented in an experimental murine model of lupus, in which they are associated with immunopathology. Here, we demonstrate the presence of antibodies against non-bilayer phospholipid arrangements containing mycolic acids in the sera of lepromatous leprosy (LL) patients, but not those of healthy volunteers. The presence of antibodies that recognise these non-bilayer lipid arrangements may contribute to the hypergammaglobulinaemia observed in LL patients. We also found IgM and IgG anti-cardiolipin antibodies in 77% of the patients. This positive correlation between the anti-mycolic-non-bilayer arrangements and anti-cardiolipin antibodies suggests that both types of antibodies are produced by a common mechanism, as was demonstrated in the experimental murine model of lupus, in which there was a correlation between the anti-non-bilayer phospholipid arrangements and anti-cardiolipin antibodies. Antibodies to non-bilayer lipid arrangements may represent a previously unrecognised pathogenic mechanism in LL and the detection of these antibodies may be a tool for the early diagnosis of LL patients.

Lepromatous leprosy patients produce antibodies that recognise non-bilayer lipid arrangements containing mycolic acids.

Non-bilayer phospholipid arrangements are three-dimensional structures that form when anionic phospholipids with an intermediate structure of the tubular hexagonal phase II are present in a bilayer of lipids. Antibodies that recognise these arrangements have been described in patients with antiphospholipid syndrome and/or systemic lupus erythematosus and in those with preeclampsia; these antibodies have also been documented in an experimental murine model of lupus, in which they are associated with immunopathology. Here, we demonstrate the presence of antibodies against non-bilayer phospholipid arrangements containing mycolic acids in the sera of lepromatous leprosy (LL) patients, but not those of healthy volunteers. The presence of antibodies that recognise these non-bilayer lipid arrangements may contribute to the hypergammaglobulinaemia observed in LL patients. We also found IgM and IgG anti-cardiolipin antibodies in 77% of the patients. This positive correlation between the anti-mycolic-non-bilayer arrangements and anti-cardiolipin antibodies suggests that both types of antibodies are produced by a common mechanism, as was demonstrated in the experimental murine model of lupus, in which there was a correlation between the anti-non-bilayer phospholipid arrangements and anti-cardiolipin antibodies. Antibodies to non-bilayer lipid arrangements may represent a previously unrecognised pathogenic mechanism in LL and the detection of these antibodies may be a tool for the early diagnosis of LL patients.

Analysis of the structure of mycolic acids of Mycobacterium simiae reveals a particular composition of alpha-mycolates in strain 'habana' TMC 5135, considered as immunogenic in tuberculosis and leprosy.

Structural analysis of mycolic acids from Mycobacterium simiae (including some 'habana' strains) was carried out using (1)H-NMR and MS. Results indicated that this species presents a general pattern of alpha-, alpha'- and keto-mycolates. alpha-Mycolates were composed of a complex mixture of 82 to 89 carbon atoms (C82-C89), with the predominant molecular species containing two di-substituted cyclopropane rings. Among keto-mycolates (C84-C89), those containing one trans di-substituted cyclopropane ring were the most abundant. The alpha'-mycolates were monounsaturated (C64, C66). According to MS and (1)H-NMR data, the strains studied differed in fine structural details of alpha-mycolates and keto-mycolates. Notably, strain 'habana' TMC 5135 (belonging to the 'habana' group, and considered as highly immunogenic in tuberculosis and leprosy) presented a particular composition of alpha-mycolates, with a major component (C87) containing one cis plus one trans di-substituted cyclopropane ring, unlike the type strain of M. simiae and other strains of the 'habana' group (IPK-220 and IPK-337R), in which the major component (C84) contained two cis di-substituted cyclopropane rings. In spite of this finding, the 'habana' strains were closely related to each other and mainly differed from the type strain of M. simiae in some details of the fine structure of keto-mycolates. The present work indicated that within an identical general pattern of mycolic acids, there is a complex composition in M. simiae and structural variation among different strains, as reported for pathogenic species of the genus. Noteworthy was the particular composition of alpha-mycolates in strain 'habana' TMC 5135.

Analysis of the structure of mycolic acids of Mycobacterium simiae reveals a particular composition of a-mycolates in strain ‘habana TMC 5135, considered as immunogenic in tuberculosis and leprosy

Structural analysis of mycolic acids from Mycobacterium simiae (including some 'habana' strains) was carried out using (1)H-NMR and MS. Results indicated that this species presents a general pattern of alpha-, alpha'- and keto-mycolates. alpha-Mycolates were composed of a complex mixture of 82 to 89 carbon atoms (C82-C89), with the predominant molecular species containing two di-substituted cyclopropane rings. Among keto-mycolates (C84-C89), those containing one trans di-substituted cyclopropane ring were the most abundant. The alpha'-mycolates were monounsaturated (C64, C66). According to MS and (1)H-NMR data, the strains studied differed in fine structural details of alpha-mycolates and keto-mycolates. Notably, strain 'habana' TMC 5135 (belonging to the 'habana' group, and considered as highly immunogenic in tuberculosis and leprosy) presented a particular composition of alpha-mycolates, with a major component (C87) containing one cis plus one trans di-substituted cyclopropane ring, unlike the type strain of M. simiae and other strains of the 'habana' group (IPK-220 and IPK-337R), in which the major component (C84) contained two cis di-substituted cyclopropane rings. In spite of this finding, the 'habana' strains were closely related to each other and mainly differed from the type strain of M. simiae in some details of the fine structure of keto-mycolates. The present work indicated that within an identical general pattern of mycolic acids, there is a complex composition in M. simiae and structural variation among different strains, as reported for pathogenic species of the genus. Noteworthy was the particular composition of alpha-mycolates in strain 'habana' TMC 5135(AU)

Análisis estructural de ácidos mycolic de Mycobacterium simiae (incluidos algunos' habana 'cepas) se llevó a cabo mediante (1) H-RMN y MS. Los resultados indican que esta especie presenta un patrón general de alfa-, y alpha'-ceto-mycolates. alfa-Mycolates se compone de una mezcla compleja de 82 a 89 átomos de carbono (C82-C89), con la predominante especies moleculares que contienen dos di-sustituidos cyclopropane anillos. Entre ceto-mycolates (C84-C89), los que contengan un transporte di-sustituidos cyclopropane anillo son los más abundantes. El alpha'-mycolates se monoinsaturados (C64, C66). EM y de acuerdo con (1) H-RMN de datos, las cepas estudiadas difieren en los detalles estructurales multa de alfa-ceto-mycolates y mycolates. En particular, la cepa 'habana' TMC 5135 (pertenecientes a la 'habana' grupo, y consideradas como altamente inmunogénica de la tuberculosis y la lepra), presentó una composición de alfa-mycolates, con un importante componente (C87) con un más uno cis trans di -sustituidos cyclopropane anillo, a diferencia de la cepa tipo de M. simiae y otras cepas de la "habana Grupo (IPK-220-337R y IPK), en la que el componente principal (C84), que figura dos di-cis sustituido cyclopropane anillos. A pesar de este hallazgo, la 'habana' cepas están estrechamente relacionadas entre sí y sobre todo diferente de la cepa tipo de M. simiae en algunos detalles de la estructura fina de ceto-mycolates. El presente trabajo se indica que dentro de un mismo patrón general de mycolic ácidos, hay una compleja composición de M. simiae y la variación estructural entre las diferentes cepas, como se informa de las especies patógenas del género. Destaca la particular composición de la alfa-mycolates en tensión 'habana' TMC 5135

Evidence for human CD4+ T cells in the CD1-restricted repertoire: derivation of mycobacteria-reactive T cells from leprosy lesions.

Both the CD4-CD8- (double negative) and CD4-CD8+ T cell lineages have been shown to contain T cells which recognize microbial lipid and glycolipid Ags in the context of human CD1 molecules. To determine whether T cells expressing the CD4 coreceptor could recognize Ag in the context of CD1, we derived CD4+ T cell lines from the lesions of leprosy patients. We identified three CD4+ Mycobacterium leprae-reactive, CD1-restricted T cell lines: two CD1b restricted and one CD1c restricted. These T cell lines recognize mycobacterial Ags, one of which has not been previously described for CD1-restricted T cells. The response of CD4+ CD1-restricted T cells, unlike MHC class II-restricted T cells, was not inhibited by anti-CD4 mAb, suggesting that the CD4 coreceptor does not impact positive or negative selection of CD1-restricted T cells. The CD4+ CD1-restricted T cell lines produced IFN-gamma and GM-CSF, the Th1 pattern of cytokines required for cell-mediated immunity against intracellular pathogens, but no detectable IL-4. The existence of CD4+ CD1-restricted T cells that produce a Th1 cytokine pattern suggests a contributory role in immunity to mycobacterial infection.