S82: Harnessing the thiostrepton biosynthetic enzymes

Thiostrepton A, produced by Streptomyces laurentii, is a prototypical example of the thiopeptide metabolites, a family of structurally complex peptides that demonstrate promising antibacterial and antimalarial activities. The development of a clinically useful thiopeptide, however, will require structural alterations in order to overcome the poor water solubility of the naturally-occurring metabolites. The thiopeptides, including thiostrepton A, were recently revealed to be the products of genetically-encoded precursor peptides subjected to extensive post-translational modification. Site-directed mutagenesis of the precursor peptide is a promising strategy to generate thiopeptide analogs, offering a tool complementary to that of semisynthetic modification. Early studies revealed that mutagenesis of the thiostrepton A precursor peptide, TsrA, provided biologically-active thiostrepton derivatives. Recent progress in the engineering of thiostrepton A variants, and the resulting insights into its biosynthesis, will be discussed.