"As humans, we anticipate that evolution perfects the end product, and so you'd expect the final molecule to be the best antibiotic, and the intermediates to be less potent,"
"is a great example of what a 'blind watchmaker' evolution is. And it's a good way of exemplifying it in a very molecular way,"
"the potential of such studies to identify new bioactive chemical scaffolds from 'old' pathways"
Streptomyces coelicolor produces methylenomycin A via a multi-step biosynthetic pathway. An intermediate compound, premethylenomycin C lactone, shows antimicrobial activity about 100 times stronger than the final antibiotic. Tiny doses of the intermediate killed bacterial strains that cause hard-to-treat infections. Sequential deletion of genes encoding pathway enzymes enabled mapping of the mechanism, with efforts beginning in 2006 and pathway mapping achieved by 2010, building on a 2002 genome sequence. Antimicrobial resistance threatens millions of deaths over coming decades, and discovery of potent intermediates highlights opportunities to derive new drug scaffolds from established biosynthetic pathways.
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