Cracking the Polyketide Code

PLoS Biology | http://biology.plosjournals.org For half a century, natural products from microorganisms have been the main source of medicines for treating infectious disease. The most important chemical class of these antibiotics, apart from the penicillins, is the polyketides. They are made by the stepwise building of long carbon chains, two atoms at a time, by multifunctional enzymes that determine the chain length, oxidation state, and pattern of branching, cyclisation, and stereochemistry of the molecules in a combinatorial fashion to produce an enormous variety of structures. Recent elucidation of the genetic ‘programming’ of the enzymes has opened a new fi eld of drug discovery based on rationally engineering the enzymes to produce ‘unnatural natural products’ with novel properties. Following the development of penicillin for the treatment of septicemia in the early 1940s, numerous antibiotics were discovered and introduced into medicine. While a fungus makes penicillin, semisynthetic derivatives of which have been a mainstay of antibacterial therapy for decades, most natural antibacterial antibiotics come from a group of soildwelling, fi lamentous bacteria called the actinomycetes, of which Streptomyces is the best-known genus. These organisms make an amazing array of so-called secondary metabolites that have evolved to give their producers a competitive advantage in the complex soil environment, where they are exposed to stresses of all kinds (Challis and Hopwood 2003). The compounds have many functions, but those Primer