P101: Biosynthetic studies on the platensimycin and platencin antibiotics

Platensimycin (PTM) and platencin (PTN) are recently discovered secondary metabolites produced by Streptomyces platensis. They are potent, selective inhibitors of bacterial and mammalian fatty acid synthases and have emerged as promising drug leads for both antibacterial and antidiabetic therapies. We have previously cloned and sequenced the genetic loci responsible for PTM/PTN production in S. platensis MA7327 and PTN production in S. platensis MA7339 to reveal genes involved in biosynthesis, regulation, and resistance. Here we present our current studies on (i) PTM and PTN biosynthesis to uncover new chemistry and enzymology inherent with unprecedented molecular scaffolds, (ii) the divergence in the PTM and PTN biosynthetic pathway dictated by novel terpenoid synthases, and (iii) PTM and PTN self-resistance mechanisms in the producers, serving as an excellent model to understand and thereby predict future PTM or PTN resistance in clinical settings. The PTM and PTN biosynthetic machineries offer a unique opportunity to study how secondary metabolic pathway evolution increases natural product structural diversity. The outcomes of these studies promise not only in-depth understanding of the biosynthetic reactions leading to PTM/PTN production but the potential for key advances in preparing PTM, PTN, and future analogs for the clinic.