Novel transformations in the biosynthesis of the marine‐derived antibiotic marinopyrrole

Abstract

The marine‐derived natural product marinopyrrole has strong promise as an antibiotic, possessing activity against methicillin‐resistant Staphylococcus aureus (MRSA). Further, the chemical structure of marinopyrrole is unprecedented among natural products, consisting of two richly halogenated pyrrolic “monomers” dimerized to give an axially chiral bispyrrole structure [Org. Lett. (2008) 10: 629–631]. We are investigating the biosynthetic origins of this molecule with two purposes in mind. First, an elucidation of the biosynthesis of marinopyrrole will enable us to embark on bioengineering experiments to generate marinopyrrole derivatives with improved antibiotic properties. Second, an understanding of how the key chemical features of the molecule, including the axis of chirality and the halogenation pattern, are enzymatically generated will provide fundamental insights into the enzymology of this particular pathway and insights into antibiotic biosynthesis more generally. To isolate the biosynthetic gene cluster for marinopyrrole, we generated and screened a cosmid library of genomic DNA from the producing organism, and sequenced two cosmids containing overlapping portions of the marinopyrrole biosynthetic cluster. The assembled cluster of ~40 kbp consists largely of enzymes with high sequence identity with those found in the pyrrolomycin biosynthetic gene cluster [Antimicrob. Agents Chemother. (2007) 51: 946–957], in addition to candidates for catalyzing the unique coupling reaction.