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.