Discovery and biosynthesis of specialized metabolites produced by an indigenous streptomyces strain

Abstract

Microbial natural product discovery was revitalized in recent years driven by the discovery of cryptic secondary metabolite biosynthetic pathways. For my Ph.D. study, I focused on the quarry lake-dwelling Streptomyces tasikensis P46 strain for natural product discovery. My research led to the discovery of tasikamides A-G, a novel family of non-ribosomal peptides that share a unique pentapeptide scaffold. A surprising hydrazone group was found in tasikamides A-C that joins the cyclic peptide scaffold to an alkyl 5-hydroxyanthranilate (AHA) moiety. We discovered that the biosynthesis of tasikamides A-C involves two pathways that produce the cyclic peptide scaffold and the AHA moiety, respectively. We elucidated a novel mechanism whereby tasikamides A-C are biosynthesized via pathway coupling and an unprecedented in vivo Japp-Klingemann reaction. Besides tasikamides, I also discovered a new polyketide-terpenoid hybrid natural product (furaquinocin K) and proposed a novel regulatory mechanism that involves the deamination of an intermediate via diazotization.