ChemInform Abstract: The Vancomycin Group of Antibiotics and the Fight Against Resistant Bacteria

This review is an account of the discoveries in the Cambridge group of the structures and mode of action of the glycopeptide antibiotics of the vancomycin group. These antibiotics are now of enormous clinical importance, for among their members are two (vancomycin and teicoplanin) of the three antibiotics of last resort against resistant bacterial pathogens (particularly methicillin-resistant Staphylococcus aureus (MRSA, or “superbugs”)) in our hospitals, which would otherwise often be lethal. Their combined sales are of the order of US$1 billion per annum. The structure determination in our laboratory started just over 25 years ago. Within ten years the first glycopeptide structures had been determined. This was quickly followed by the determination of the molecular basis of their action, through the making of five hydrogen bonds to a cell wall peptide precursor that terminated in -Lys-d-Ala-d-Ala. In the early 1990s, we established that all the glycopeptides so far examined (other than teicoplanin) form dimers, and shortly after showed that dimerization promotes antibiotic activity. Concurrently, we were able to demonstrate that teicoplanin possesses a membrane anchor that can act to promote antibiotic activity in lieu of dimerization. The devices of dimerization and membrane anchoring, when acting concurrently, appear to be able to account at least in part for the remarkable activity of a new semi-synthetic glycopeptide—developed at Eli Lilly—against bacteria that are resistant even to vancomycin. A full understanding of these devices is important, since occurrences of the “nightmare scenario” that clinicians have feared over recent years—that resistance to vancomycin will appear in new forms of MRSA—have recently been reported.