Mycolactones: immunosuppressive and cytotoxic polyketides produced by aquatic mycobacteria

Abstract

Mycolactones are a family of highly related macrocyclic polyketides that exhibit immunosuppressive and cytotoxic properties. First discovered in 1999, they are the primary virulence factors produced by the environmental human pathogen Mycobacterium ulcerans, the causative agent of Buruli ulcer, and by some closely-related aquatic mycobacteria that cause disease in fish and frogs. Mycolactones are characterized by a common 12-membered lactone core to which is appended an unsaturated fatty acyl side-chain of variable length and oxidation state. This Highlight summarizes recent progress in understanding the structural diversity of the mycolactones, their biological activity and mode of action in mammalian cells, and the genetics, evolution, and enzymology of their biosynthesis.

Hui Hong

Tim Stinear

Fig. 1. Mycolactone variations represented by the five naturally occurring structures (A/B–F) and one unnatural structure (G). The stereochemistry of the core is assumed to remain the same but has yet to be established for mycolactones D and E.

Fig. 2. Summary of the known effects of mycolactones on various mammalian cell types. Abbreviations LPS: lipopolysaccharide; TNF: tumour necrosis factor; IL: interleukin; NF-κB: nuclear factor kappa B.

Fig. 3. Genetic organisation of the mycolactone biosynthetic PKS gene loci derived from the complete sequences of pMUM001 (from a mycolactone A/B producer, M. ulcerans Agy99) and pMUM002 (from the mycolactone E producer, Mycobacterium liflandii 128FXT) and proposed from the structure of mycolactone D and the partial sequence of the mlsB gene of M. ulcerans strain 980912 (region sequenced shown in colour). The predicted enzymatic domain specificity derived from each of the three proteins (MlsA1, MlsA2 and MlsB) is represented by a coloured block whose predicted function is outlined in the key. Module arrangements are shown below each gene, and modules are colour-coded to reflect the combination of domains they possess. Crosses through dehydratase domains indicate that they are predicted to be inactive based on a mutation in the active site sequence. All identically coloured domains share 97–100% aa sequence identity.