A Novel Mycolactone Toxin Obtained by Biosynthetic Engineering

University of Cambridge, Cambridge, England, United Kingdom
ChemBioChem (Impact Factor: 3.09). 11/2007; 8(17):2043-7. DOI: 10.1002/cbic.200700411
Source: PubMed


A novel structural variant of the mycobacterial polyketide toxin mycolactone has been obtained by cloning a P450 hydroxylase gene from a related strain. This technique increases the range of available mycolactones for studies on the mode of action of the toxin.

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    • "Non-cytotoxic levels of ROS could be responsible for inhibitory effects on immune cells. For example, mycolactone inhibits IL-2 production by T cells [24], [25] and TNF-production by monocytes [26] . Such immunosuppressive effects by mycolactone would prevent an immune system mediated elimination of bacteria from infected tissue. "
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    ABSTRACT: Mycobacterium ulcerans is the causative agent of necrotizing skin ulcerations in distinctive geographical areas. M. ulcerans produces a macrolide toxin, mycolactone, which has been identified as an important virulence factor in ulcer formation. Mycolactone is cytotoxic to fibroblasts and adipocytes in vitro and has modulating activity on immune cell functions. The effect of mycolactone on keratinocytes has not been reported previously and the mechanism of mycolactone toxicity is presently unknown. Many other macrolide substances have cytotoxic and immunosuppressive activities and mediate some of their effects via production of reactive oxygen species (ROS). We have studied the effect of mycolactone in vitro on human keratinocytes--key cells in wound healing--and tested the hypothesis that the cytotoxic effect of mycolactone is mediated by ROS. The effect of mycolactone on primary skin keratinocyte growth and cell numbers was investigated in serum free growth medium in the presence of different antioxidants. A concentration and time dependent reduction in keratinocyte cell numbers was observed after exposure to mycolactone. Several different antioxidants inhibited this effect partly. The ROS inhibiting substance deferoxamine, which acts via chelation of Fe(2+), completely prevented mycolactone mediated cytotoxicity. This study demonstrates that mycolactone mediated cytotoxicity can be inhibited by deferoxamine, suggesting a role of iron and ROS in mycolactone induced cytotoxicity of keratinocytes. The data provide a basis for the understanding of Buruli ulcer pathology and the development of improved therapies for this disease.
    Full-text · Article · Nov 2010 · PLoS ONE
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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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