Platensimycin and platencin: promising antibiotics for future application in human medicine

Abstract

Platensimycin and platencin are novel antibiotics produced by Streptomyces platensis. They are potent and non-toxic natural products active against Gram-positive pathogens, including antibiotic-resistant strains and Mycobacterium tuberculosis. They were isolated using an intriguing target-based whole-cell antisense differential sensitivity assay as inhibitors of fatty acid biosynthesis of type II. This type of biosynthesis is not present in humans. Platensimycin inhibits the elongation-condensing enzyme FabF, whereas platencin inhibits both FabF and FabH. For these antibiotics to become successful drugs, their pharmacokinetics must be improved. They have too high a rate of clearance in the body, yielding a low degree of systematic exposure. They work well when administered by continuous infusion, but this is not a useful method of delivery to patients. The two antibiotics and many analogs have been prepared by chemical synthesis. Natural congeners have also been obtained from the producing actinomycete. However, none of these molecules are as active as platensimycin and platencin. Using tools of rational metabolic engineering, superior strains have been produced making hundreds of times more antibiotic than the natural strains.

Discovery of novel FabF ligands inspired by platensimycin by integrating structure-based design with diversity-oriented synthetic accessibility

“…24 Several total syntheses of platensimycin, [27][28][29] as well as a related natural product platencin, 30 have been reported. Additionally, analogues of platensimycin have been synthesised, [31][32][33][34][35] allowing the definition of structure-function relationships. In most cases, even small modifications of the polar aromatic headgroup lead to a dramatic reduction in biological activity.…”

Microbial synthetic biology for human therapeutics

“…The last decade witnessed the emergence of only two novel classes of antibiotics namely lipopeptide and oxazolidinone (Norrby et al 2005). In 2006, a promising antibiotic molecule, platensimycin, was also discovered however, it could not reach clinical trials due to its poor pharmacokinetic properties (Pearson 2006;Martin and Demain 2011). Lipopeptide and oxazolidinones are active against gram positive bacteria such as vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus.…”

Titer improvement and pilot-scale production of platensimycin from Streptomyces platensis SB12026

“…Therefore, PTM and PTN are promising drug leads for human medicine. However, their poor in vivo pharmacokinetics has significantly limited the future drug development and none of their analogs prepared so far showed superior activities (Martens and Demain, 2011). In addition, the low titer of PTM or PTN from the wild-type strains limited their production, thereby preventing cost-effective preparation of analogues via semi-synthesis methods (Herath et al 2008; Shen et al 2009).…”