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

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.