Buruli toxin genes decoded.

T he ancient scourges of leprosy and tuberculosis are diseases caused by mycobacteria. These afflictions remain widespread in much of the world. It is estimated that one-third of Earth’s population is infected with tuberculosis, and 2 million die of the active form of the disease annually. Tuberculosis claims the greatest number of victims of any infectious disease and has reawakened public health concerns everywhere with the emergence of multiply drug-resistant strains. A lesser-known but devastating skin disease known as Buruli ulcer is caused by Mycobacterium ulcerans. This human pathogen is carried by aquatic insects (1), and the occurrence of the disease is spreading in central and west Africa, where its incidence now exceeds that of leprosy and is similar to tuberculosis in highly affected areas. Infection with M. ulcerans causes progressive necrotic lesions that, if untreated, can extend to 15% of a victim’s body and lead to lifelong disability and occasionally death. Curiously, even advanced disease is usually marked by little inflammatory response and no physical pain. Pathogenesis by M. ulcerans is caused by the secretion of a small family of lipophilic toxins exemplified by mycolactones A and B. In this issue of PNAS, Stinear et al. (2) report the isolation and characterization of a biosynthetic cluster comprising six genes, three of which encode giant polyketide synthases (PKSs) that are central to mycolactone production. Their discovery reveals several highly unusual features of this virulence system and these proteins. Genetic subtraction experiments led to identification of the M. ulceransspecific PKS genes (3). Unexpectedly, Stinear et al. found that the PKS genes are harbored in a large, 174-kb plasmid, whose primary function appears to be mycolactone production. This is the first reported example of plasmidmediated virulence in a Mycobacterium. In addition, complete decoding and translation of the biosynthetic gene