Studies on the Mycolic Acids from the Walls of Mycobacterium microti

Davidson, Leslie A.; Draper, P.; Minnikin, David E.

doi:10.1099/00221287-128-4-823

Cited by 32 publications

(43 citation statements)

References 14 publications

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“…Thus changes in the proportion of methoxy-and keto-MA had already been reported during cultivation of Mycobacterium microti [26]. In a second landmark paper, Watanabe et al identified and collated the positions of the functional groups in the meromycolate fragments of the MA, revealing the full complexity of the mixtures present and again showing considerable difference between H37Ra and other M.tuberculosis strains [25].…”

Section: Structural Properties Of Mycolic Acids Of Mycobacterium Specmentioning

confidence: 82%

Towards understanding the functional diversity of cell wall mycolic acids of Mycobacterium tuberculosis

Verschoor

Baird

Grooten

2012

Progress in Lipid Research

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Mycolic acids constitute the waxy layer of the outer cell wall of Mycobacterium spp and a few other genera. They are diverse in structure, providing a unique chromatographic foot-print for almost each of the more than seventy Mycobacterium species. Although mainly esterified to cell wall arabinogalactan, trehalose or glucose, some free mycolic acid is secreted during in vitro growth of M. tuberculosis. In M. tuberculosis, alpha-, keto-and methoxy-mycolic acids are the main classes, each differing in their ability to attract neutrophils, induce foamy macrophages or adopt an antigenic structure for antibody recognition. Of interest is their particular relationship to cholesterol, discovered by their ability to attract cholesterol, to bind Amphotericin B or to be recognised by monoclonal antibodies that cross-react with cholesterol. The structural elements that determine this diverse functionality include the carboxylic acid in the mycolic motif, as well as the nature and stereochemistry of the two functional groups in the merochain. The functional diversity of mycolic acid classes implies that much information may be contained in the selective expression and secretion of mycolic acids to establish tuberculosis after infection of the host. Their cholesteroid nature may relate to how they utilize host cholesterol for their persistent survival.

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Section: Structural Properties Of Mycolic Acids Of Mycobacterium Specmentioning

confidence: 82%

Towards understanding the functional diversity of cell wall mycolic acids of Mycobacterium tuberculosis

Verschoor

Baird

Grooten

2012

Progress in Lipid Research

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“…Little is known about how mycolic acid production is regulated. However, it has been shown that mycolic acid composition ratios vary at different growth phases in vitro, during intracellular growth, and at temperature shifts (2,9,17,31,34). Whether feedback inhibition mechanisms maintain the mycolate composition ratio in the cell wall (alpha to methoxy) in wild-type strains remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

“…However, production by other pathogenic mycobacteria varies. What is striking is that virtually all pathogenic mycobacteria produce ketomycolates and that ketomycolate production is increased in vivo (9). It was recently shown that inhalation exposure of guinea pigs to purified methyl ketomycolates but not methyl methoxymycolates or methyl alpha-mycolates induced pulmonary granulomas (30).…”

Section: Discussionmentioning

confidence: 99%

Impact of Methoxymycolic Acid Production by Mycobacterium bovis BCG Vaccines

et al. 2004

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BCG vaccines are a family of closely related daughter strains of an attenuated isolate of Mycobacterium bovis derived by in vitro passage from 1908 to 1921. During subsequent laboratory propagation of the vaccine strain until its lyophilization in 1961, BCG Pasteur underwent at least seven further genomic mutations. The impact of these mutations on the properties of the vaccine is currently unknown. One mutation, a glycine-to-aspartic acid substitution in the mmaA3 gene, occurred between 1927 and 1931 and impairs methoxymycolic acid synthesis in BCG strains obtained from the Pasteur Institute after this period. Mycolic acids of the cell wall are classified into three functional groups (alpha-, methoxy-, and ketomycolic acids), and together these lipids form a highly specialized permeability barrier around the bacterium. To explore the impact of methoxymycolic acid production by BCG strains, we complemented the functional gene of mmaA3 into BCG Denmark and tested a number of in vitro and in vivo phenotypes. Surprisingly, restoration of methoxymycolic acids alone had no effect on cell wall permeability, resistance to antibiotics, or growth in cultured macrophages and C57BL/6 mice. Our results demonstrate that the loss of methoxymycolic acid production did not apparently affect the virulence of BCG strains.Bacille Calmette-Guérin (BCG) vaccines are live attenuated strains of Mycobacterium bovis derived by in vitro passage from 1908 to 1921. BCG vaccines are given to millions of infants each year as antituberculosis vaccines, although their capacity to prevent tuberculosis in clinical trials has ranged from 80% protection to no detectable benefit (11). Several hypotheses have been proposed to explain this variable protection, including exposure to environmental mycobacteria (26) and differences between BCG vaccine strains (8).From genomic analyses, it is now known that during in vitro passage, M. bovis lost a genomic region called RD1 (19), which has been shown to contribute to the observed attenuation of virulence of M. bovis BCG strains (16,27). However, complementation of RD1 in the Pasteur strain of BCG did not completely restore pathogenicity in immunocompetent mice (27), suggesting that further mutations contribute to the observed phenotype of BCG strains. Because BCG stocks were propagated for another 40 to 50 years in various vaccine production laboratories, it has been hypothesized that ongoing evolution of BCG in vitro may have resulted in additional attenuation to the detriment of protective efficacy (5). Early reports on BCG suggest a second phase of attenuation in the late 1920s (24), with a decrease in BCG virulence in animal models (15) and reduced persistence of BCG in the mesenteric lymph nodes of vaccinated children (35). These observations are consistent with recent genomic analysis of existing BCG strains that revealed numerous mutations occurring after 1921 (6, 23).Further evidence of evolution of BCG strains followed from studies demonstrating the loss of methoxymycolic acid production in BCG P...

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“…7, step 4), which could be the hydroxymycolate or a precursor. The existence of a common precursor for the keto-and the methoxy-mycolic acids would account for the equilibrium observed between the amounts of these two types of mycolate synthesized during the growth of Mycobacterium microti (Davidson et al, 1982).…”

Section: Discussionmentioning

confidence: 99%

Mycobacteriumbovis BCG genes involved in the biosynthesis of cyclopropyl keto‐ and hydroxy‐mycolic acids

Dubnau¹,

Lanéelle

Soares³

et al. 1997

Molecular Microbiology

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SummaryThe resurgence of tuberculosis and the emergence of multidrug-resistant mycobacteria necessitate the development of new antituberculosis drugs. The biosynthesis of mycolic acids, essential elements of the mycobacterial envelope, is a good target for chemotherapy. Species of the Mycobacterium tuberculosis complex synthesize oxygenated mycolic acids with keto and methoxy functions. In contrast, the fastgrowing Mycobacterium smegmatis synthesizes oxygenated mycolic acids with an epoxy function. We describe the isolation and sequencing of a cluster of four genes from Mycobacterium bovis bacillus Calmette-Gué rin (BCG), coding for methyl transferases, and which, when transferred into M. smegmatis, allow the synthesis of ketomycolic acid, in addition to an as yet undescribed mycolic acid, hydroxymycolic acid. These oxygenated mycolic acids, unlike the regular mycolic acids of M. smegmatis, and similar to the mycolic acids of M. bovis, are highly cyclopropanated. Furthermore, there is a perfect match between the structures of the keto-and the hydroxy-mycolic acids. We propose a biosynthetic model in which there is a direct relationship between these two types of mycolic acid.

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Studies on the Mycolic Acids from the Walls of Mycobacterium microti

Cited by 32 publications

References 14 publications

Towards understanding the functional diversity of cell wall mycolic acids of Mycobacterium tuberculosis

Towards understanding the functional diversity of cell wall mycolic acids of Mycobacterium tuberculosis

Impact of Methoxymycolic Acid Production by Mycobacterium bovis BCG Vaccines

Mycobacteriumbovis BCG genes involved in the biosynthesis of cyclopropyl keto‐ and hydroxy‐mycolic acids

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