Mycolactone

Mycolactone is a polyketide-derived macrolide produced and secreted by a group of very closely related pathogenic mycobacteria species including M. ulcerans, M. liflandii (an unofficial designation), M. pseudoshottsii, and some strains of M. marinum. These mycobacteria are collectively referred to as mycolactone-producing mycobacteria or MPM.

In humans, mycolactone is the toxin responsible for Buruli ulcers, doing so by damaging tissues and inhibiting the immune response.

History

Early observations

In the 1960s, pathologists studying Buruli ulcer in Uganda noted extensive tissue necrosis with very little inflammation extending beyond bacterial clusters, suggesting secretion of a diffusible cytotoxin by Mycobacterium ulcerans.

Discovery and characterization

In 1999, George and colleagues purified this factor from alcohol-soluble lipids and identified a 12-membered macrolactone with two polyketide side chains, naming it mycolactone (from its mycobacterial origin and macrolactone structure). It was the first polyketide macrolide isolated from a mycobacterium and the first identified polyketide virulence factor of a human pathogen. In 2002, the total synthesis of the molecule was done by Song et al. and enabled the creation of synthetic variants for laboratory study.

Evolving understanding (2000s - Present)

Research in the early 2000s identified that the genetic instructions for mycolactone reside on a giant virulence plasmid, pMUM001. Researchers also discovered that naturally occurring mycolactone consists of several structural variants, primarily isomers A and B (Z/E at C4′–C5′), with absolute stereochemistry confirmed by total synthesis.

Subsequent studies identified additional congeners (C–F and beyond) from strains of different geographic origins.