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Infection and Immunity, February 2003, p. 774-783, Vol. 71, No. 2
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.2.774-783.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Heterogeneity of Mycolactones Produced by Clinical Isolates of Mycobacterium ulcerans: Implications for Virulence

Institute of Tropical Medicine, B-2000 Antwerp, Belgium,¹ Department of Microbiology, University of Tennessee, Knoxville, Tennessee 37996,² Department of Pharmaceutical Sciences, Health Science Center, University of Tennessee, Memphis, Tennessee 38163,³ Rocky Mountain Laboratories, Hamilton, Montana 59840⁴

Received 9 July 2002/ Returned for modification 25 September 2002/ Accepted 15 November 2002

Mycobacterium ulcerans is the causative agent of Buruli ulcer, a severe necrotizing skin disease endemic in tropical countries. Clinical evidence suggests that M. ulcerans isolates from Asia, Mexico, and Australia may be less virulent than isolates from Africa. In vivo studies suggest that mycolactone, a polyketide-derived macrolide toxin, plays a major role in the tissue destruction and immune suppression which occur in cases of Buruli ulcer. Mycolactones were extracted from 34 isolates of M. ulcerans representing strains from Africa, Malaysia, Asia, Australia, and Mexico. Thin-layer chromatography, mass spectroscopic analysis, and cytopathic assays of partially purified mycolactones from these isolates revealed that M. ulcerans produces a heterogeneous mixture of mycolactone variants. Mycolactone A/B, the most biologically active mycolactone species, was identified by mass spectroscopy as [M⁺Na]⁺ at m/z 765.5 in all cytotoxic isolates except for those from Mexico. Mycolactone C [M+Na]⁺ at m/z 726.3 was the dominant mycolactone species in eight Australian isolates, and mycolactone D [M+Na]⁺ m/z 781.2 was characteristic of two Asian strains. Mycolactone species are conserved within specific geographic areas, suggesting that there may be a correlation between mycolactone profile and virulence. In addition, the core lactone, [M+Na]⁺ m/z 447.4, was identified as a minor species, supporting the hypothesis that mycolactones are synthesized by two polyketide synthases. A cytopathic assay of the core lactone showed that this molecule is sufficient for cytotoxicity, although it is much less potent than the complete mycolactone.

Editor: J. T. Barbieri