Platensimycin and Platencin Biosynthesis in Streptomyces platensis: Exploring Nature's Biological Machinery for the Discovery and Development of Useful Compounds.

摘要

Platensimycin (PTM) and platencin (PTN) are recently discovered secondary metabolites produced by strains of 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. In addition to traditional medicinal chemistry approaches to lead small molecule optimization for drug development, characterization of the organisms responsible for production of complex natural products complements synthetic efforts. Advantages of studying the biosynthetic pathways of antibiotic small molecules include (i) discovery of novel enzymes providing access to new chemistry, biochemistry and mechanisms of catalysis; (ii) discovery of regulatory elements providing methods for increasing titers of lead compounds; (iii) identification of self-resistance mechanisms providing insight for prediction and prevention of clinical resistance; and finally, (iv) identification of opportunities for combinatorial biosynthesis, pathway engineering, and improved methods of drug discovery and development. The genetic loci responsible for PTM/PTN production in S. platensis MA7327 and PTN production in S. platensis MA7339 were cloned and sequenced to reveal genes involved in biosynthesis, regulation, and resistance. Ultimately, the structural differences between PTM and PTN lie in their unique diterpenoid moieties. Herein, the divergence in the PTM and PTN biosynthetic pathways dictated by novel diterpene synthases is explored as the producing strains of PTM and PTN present a unique opportunity for the comparative study of biosynthetic pathways producing related -- but distinct -- compounds. By studying the strategies Nature employs for increasing structural diversity in secondary metabolic pathways, we may gain insight into exploiting these strategies for developing methods for generating new and useful compounds. Additionally, the self-resistance mechanisms in the producing organisms of PTM and PTN are presented and serve as excellent models to understand and thereby predict future resistance mechanisms to new lead antibiotic compounds. The outcomes of these studies promise not only in-depth understanding of the unique biosynthetic reactions leading to PTM and PTN production but offer the potential for key advances in preparing PTM, PTN, and future analogs for the clinic.