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As antibiotics fall to bacterial resistance one by one, it is essential that medicinal chemists keep ahead of the game by finding compounds with new modes of attack. Recently a new antibiotic, platensimycin, that homes in on a new bacterial weakness was discovered by a Merck research group in a fungal brew of Streptomyces platensis. Kyriacos "KC" Nicolaou and his colleagues, Ang Li and David Edmonds at the Scripps Research Institute, La Jolla, and University of California, San Diego, have now devised a total synthesis of this unique compound and tracked their progress using mass spectrometry and NMR spectroscopy. Platensimycin inhibits an important step in bacterial fatty acid biosynthesis and so paralyses a wide range of Gram-positive bacterial strains, the group of microbes to which the likes of Staphylococcus aureus, Enterococcus faecium, and Clostridium difficile, potentially deadly bacteria that have developed drug resistance. Indeed, it is the most potent inhibitor of the elongation-condensing enzymes involved in this crucial biosynthetic step. Like many natural products isolated from microbial fungi before it, platensimycin can kill resistant pathogenic bacteria, but the novelty of its mode of action may postpone significantly the emergence of resistance. "Compounds that act through new mechanisms are particularly attractive as they offer the prospect of combating effectively infections resistant to all existing drugs," says Nicolaou. Platensimycin consists of an unusual aromatic ring structure, 3-amino-2,4-di-hydroxybenzoic acid polar domain, coupled through an amide group to a compact cage, a pentacyclic ketolide. In order to devise a total synthesis of this complex molecules, Nicolaou and his team first had to devise total syntheses of these two components, each a challenge in their own right. The aromatic compound was synthesised from a readily available starting material in just two steps, however, the cage component required a sophisticated eleven-step sequence. The final step would be to join the two sub-units together, in a single reaction step. The simplicity of this description belies the actual complexity of the retrosynthetic analyses undertaken to decide on starting materials and the reactants needed to push them towards the final product. En route, NMR and MS, of course, provide evidence of the reactions' successes and the structure of the synthesised platensimycin. "The described chemistry," says Nicolaou, "sets the stage for the synthesis of designed analogues for structure-activity relationship studies in the search for new antibacterial agents." "The next step here is to devise an asymmetric version of our synthesis and to design and synthesize analogs of platensimycin in search of an ideal pharmacological profile," KC told SpectroscopyNOW. Merck, the discoverers of the molecule, may already be in advanced studies in terms of developing a platensimycin molecule as an antibiotic. "If successful, such studies will ensure our defence against super bugs for a while," KC adds, "but we must always be mindful that this victory may also be a temporary one in our struggle against these ever-evolving pathogens." Related links: |
 Nicolaou, on a synthetic odyssey
 Platensimycin, superbug slayer |
