A Novel Mycolactone Toxin Obtained by Biosynthetic Engineering

Sanger Building, Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1QW, UK.
ChemBioChem (Impact Factor: 3.06). 11/2007; 8(17):2043-7. DOI: 10.1002/cbic.200700411
Source: PubMed
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Available from: Caroline Demangel, Aug 08, 2015
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    ABSTRACT: Mycobacterium ulcerans is the third most common mycobacterial infection of humans and causes a destructive disease of subcutaneous tissue known as Buruli ulcer. A cytotoxic lipid known as mycolactone mediates the characteristic necrosis seen in Buruli ulcers. A family of highly related mycolactone structural variants have been discovered, all of which are produced by large polyketide synthases (PKSs), encoded by genes on large plasmids harbored by M. ulcerans strains. The prototype mycolactone plasmid is pMUM001, a 174-kb circular molecule from a West African epidemic strain of M. ulcerans. A striking feature of pMUM001 is that it has one-third of its DNA devoted to three very large genes that encode the mycol-actone biosynthetic machinery. The plasmid (pMUM002) from M. ulcerans subsp. liflandii has recently been completely sequenced, and partial sequence has been obtained for a further pMUM plasmid, pMUM003, from M. ulcerans DL240490. Interstrain comparisons of pMUM sequences has revealed the highly mutable nature of the mycolactone PKS genes and given us greater insight into the origins of these large replicons.
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    The Lancet Infectious Diseases 08/2005; 5(7):400. DOI:10.1016/S1473-3099(05)70151-1 · 19.45 Impact Factor
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    ABSTRACT: Buruli ulcer (BU) is a progressive disease of subcutaneous tissues caused by Mycobacterium ulcerans. The pathology of BU lesions is associated with the local production of a diffusible substance, mycolactone, with cytocidal and immunosuppressive properties. The defective inflammatory responses in BU lesions reflect these biological properties of the toxin. However, whether mycolactone diffuses from infected tissues and suppresses IFN-gamma responses in BU patients remains unclear. Here we have investigated the pharmacodistribution of mycolactone following injection in animal models by tracing a radiolabeled form of the toxin, and by directly quantifying mycolactone in lipid extracts from internal organs and cell subpopulations. We show that subcutaneously delivered mycolactone diffused into mouse peripheral blood and accumulated in internal organs with a particular tropism for the spleen. When mice were infected subcutaneously with M. ulcerans, this led to a comparable pattern of distribution of mycolactone. No evidence that mycolactone circulated in blood serum during infection could be demonstrated. However, structurally intact toxin was identified in the mononuclear cells of blood, lymph nodes and spleen several weeks before ulcerative lesions appear. Importantly, diffusion of mycolactone into the blood of M. ulcerans-infected mice coincided with alterations in the functions of circulating lymphocytes. In addition to providing the first evidence that mycolactone diffuses beyond the site of M. ulcerans infection, our results support the hypothesis that the toxin exerts immunosuppressive effects at the systemic level. Furthermore, they suggest that assays based on mycolactone detection in circulating blood cells may be considered for diagnostic tests of early disease.
    PLoS Neglected Tropical Diseases 02/2008; 2(10):e325. DOI:10.1371/journal.pntd.0000325 · 4.49 Impact Factor
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