Angew. Chem. Int. Ed. 52, 7822–7824 (2013)

Few diseases carry the sinister connotations of anthrax. It is a deadly infection that predominantly affects herbivores, although it has also been used for bioterrorism and adapted for biowarfare. Anthrax is caused by Bacillus anthracis, and, like other bacterial diseases, it is normally treated with antibiotics; however, because the infection does not always respond to treatment — and because the infection needs to be completely eradicated — the course of antibiotics may need to be taken for up to six months, or as a continuous intravenous supply. This dangerous combination of a potentially lethal infection and its resistance to treatment means that new antibiotics are needed to target this bacterium.

In an effort to discover new antimicrobial scaffolds, a team led by William Fenical at the University of California at San Diego, USA, isolated metabolites from a marine organism (a species of Streptomyces) and tested them for antibacterial activity. One metabolite showed potent activity against the Gram-positive Bacillus anthracis and methicillin-resistant Staphylococcus aureus; although it had only very limited activity against Gram-negative bacteria such as Escherichia coli. A series of NMR spectroscopy, mass spectrometry and X-ray crystallography analyses enabled the team to characterize the structure and stereochemistry of this new antimicrobial compound — which they termed anthracimycin. The compound has an unusual triple-ring system formed from 14, 6 and 6 atoms, respectively, as well as an enolized β-diketone.

Although the tricyclic ring system found in anthracimycin is rare, it is not unprecedented. A related metabolite called chlorotonil features the same tricyclic ring system — along with a dichloro group on the 14-membered ring. Fenical and the team decided to incorporate this dichloro moiety into anthracimycin to see what effect this would have on the antimicrobial activity. Interestingly, the dichloro analogue was approximately half as potent against Bacillus anthracis, however, it exhibited greater activity against some strains of Gram-negative bacteria — which the team believe is linked to easier penetration through the cell wall.