Platensimycin and platencin: Inspirations for chemistry, biology, enzymology, and medicine

Abstract

Natural products have served as the main source of drugs and drug leads, and natural products produced by microorganisms are one of the most prevalent sources of clinical antibiotics. Their unparalleled structural and chemical diversities provide a basis to investigate fundamental biological processes while providing access to a tremendous amount of chemical space. There is a pressing need for novel antibiotics with new mode of actions to combat the growing challenge of multidrug resistant pathogens. This review begins with the pioneering discovery and biological activities of platensimycin (PTM) and platencin (PTN), two antibacterial natural products isolated from Streptomyces platensis. The elucidation of their unique biochemical mode of action, structure-activity relationships, and pharmacokinetics is presented to highlight key aspects of their biological activities. It then presents an overview of how microbial genomics has impacted the field of PTM and PTN and revealed paradigm-shifting discoveries in terpenoid biosynthesis, fatty acid metabolism, and antibiotic and antidiabetic therapies. It concludes with a discussion covering the future perspectives of PTM and PTN in regard to natural products discovery, bacterial diterpenoid biosynthesis, and the pharmaceutical promise of PTM and PTN as antibiotics and for the treatment of metabolic disorders. PTM and PTN have inspired new discoveries in chemistry, biology, enzymology, and medicine and will undoubtedly continue to do so.

Keywords: Biosynthesis; Fatty acid synthase; Metabolic pathway engineering; Platencin; Platensimycin.

Figure 1

Structures of PTM and PTN, inhibition of fatty acid synthase, and self-resistance in native producers. (A) Structures of PTM and PTN featuring diterpene-derived ketolides linked to 3-amino-2,4-dihydroxybenzoic acid moieties. IC₅₀ values of FabH and FabF S. aureus (Sa) and human and rat FAS. (B) Bacterial fatty acid biosynthesis catalyzed by FASII. PTM selectively inhibits FabF/B and PTN dually inhibits FabH and FabB/FabF. The two complementary mechanisms of resistance in S. platensis by target replacement (i.e., FabH and FabF by PtmP3) and target modification (i.e., native PTM-insensitive FabF).

Figure 2

Inhibition of FabF by PTM. (A) FabF (and FabH) catalyzes the decarboxylating condensation reaction in fatty acid biosynthesis using a three step ping-pong mechanism. (i) The fatty acid chain from acyl-ACP is first transferred to the active site cysteine forming an acyl-enzyme thioester intermediate and releasing free ACP. (ii) Malonyl-ACP then binds to the acyl-enzyme intermediate. (iii) Following decarboxylation of malonyl-ACP, the condensation reaction yields an acyl-ACP product that is two carbons longer than the substrate in (i). FabF is regenerated to its initial reduced state and CO₂ is released. (iv) PTM inhibits FabF by mimicking the malonyl-ACP binding interaction with the acyl-enzyme intermediate. (B) PTM bound E. coli FabF (PDB entry 2GFX [15]). The solvent-accessible surface area of FabF, colored according to electrostatic potential, is shown. PTM is shown as a ball and stick model with green carbon atoms, red oxygen atoms, and blue nitrogen atoms. (C) PTM bound in the malonate-binding pocket of FabF. Residues in the binding pocket that make key interactions (dotted black lines indicating distances of 2.6–3.2 Å) with PTM are shown as magenta sticks. The solvent-accessible surface area of FabF and PTM are shown as described in (B).

Figure 3

Current SAR model of PTM and PTN supported by selected natural, synthetic, and mutasynthetic analogues. The carbons of the ketolide moieties of PTM and PTN are numbered for reference. See Table 1 for a summary of the biological activities (MICs) of each variant shown.

Figure 4

PTM-PTN dual and PTN exclusive biosynthetic gene clusters and a unified pathway for PTM and PTN biosynthesis. ptm and ptn biosynthetic gene clusters and biosynthetic model. (A) Genetic organization of the ptm gene cluster from S. platensis MA7327 and (B) the ptn gene cluster from S. platensis MA7339. Genes are color-coded corresponding to the predicted function of the encoded proteins in biosynthesis, resistance, and regulation. The “PTM” cassette (shaded in gray), which contains five genes that bestow the ptm cluster the ability for dual production of PTM and PTN, is present in the ptm cluster and absent in the ptn cluster. (C) ADHBA biosynthesis from ASA and DHAP. (D) Diterpene-derived ketolide biosynthesis from IPP and DMAPP, from the MEP pathway. ent-CPP is the final common intermediate in the biosynthesis of PTM and PTN. ent-CPP is cyclized by two dedicated diterpene synthases, PtmT3 for PTM and PtmT1/PtnT1 for PTN, and the resultant diterpenes are processed by PTM-specific (e.g., PtmO5) or unspecific (e.g., enzymes for A-ring cleavage or β-oxidation) tailoring enzymes into the penultimate products platensicyl-CoA and platencinyl-CoA. PtmC/PtnC concludes the biosynthetic pathway by coupling ADHBA and the ketolides to afford PTM and PTN.