GLYCOPEPTIDE RESISTANCE IN MULTIPLE ANTIBIOTIC-RESISTANT GRAM-POSITIVE BACTERIA - A CURRENT CHALLENGE FOR NOVEL SEMISYNTHETIC GLYCOPEPTIDE DERIVATIVES

Resistance to the glycopeptide antibiotics vancomycin (V) and teicopla nin (T) in multi-resistant Gram-positive pathogens, particularly enter ococci, is becoming a dramatic nosocomial problem. Besides the current lack of efficacious alternative therapeutic options, a major concern is the possibility of spreading of high glycopeptide resistance from V anA enterococci to methicillin resistant Staphylococcus aureus (MRSA) and to coagulase-negative staphylococci (CNS), for which glycopeptides are still drugs of choice. In past years much effort was made in purs uit of new glycopeptide derivatives with enhanced efficacy against cli nical isolates of MRSA and CNS with decreased susceptibility to T and occasionally to V. Promising results have been obtained by structural changes which did not affect binding to the glycopeptide's target pept ide D-alanyl-D-alanine (D-Ala-D-Ala). The structure-activity relations hips (SAR) of some modified T- and V-type compounds also indicated the possibility of achieving activity against highly glycopeptide-resista nt enterococci by chemical derivatization of naturally occurring glyco peptides while maintaining unmodified the structure of the binding sit e. Recently, it has been found that the glycopeptide resistance in Van A enterococci is due to the replacement of target D-Ala-D-Ala by D-Ala -D-lactate depsipeptide in the peptidoglycan precursor. As glycopeptid e derivatives active against resistant enterococci have not been shown to have enhanced binding to the target depsipeptide, a mode of action has been hypothesized that relates to their ability to dimerize and i nteract with membranes. The understanding of the mechanism of glycopep tide resistance in VanA enterococci, and the discovery of a selective procedure for the removal of amino acids 1 and 3 from natural glycopep tides also suggested new strategies which, based on molecular modeling studies, aim at obtaining glycopeptide-derived compounds suitably mod ified in their heptapeptide structure to allow simultaneous molecular interaction with both susceptible and resistant targets. As a prelimin ary approach, novel non-natural glycopeptides in which amino acids 1 a nd 3 are replaced by new amino acids have been prepared.