Glycopeptide resistance in multiple antibiotic-resistant Gram-positive bacteria: a current challenge for novel semi-synthetic glycopeptide derivatives

Abstract

Summary Resistance to the glycopeptide antibiotics vancomycin (V) and teicoplanin (T) in multi-resistant Gram-positive pathogens, particularly enterococci, 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 VanA enterococci to methicillinresistant 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 pursuit of new glycopeptide derivatives with enhanced efficacy against clinical 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 peptide d -alanyl- d -alanine ( d -Ala- d -Ala). The structure-activity relationships (SAR) of some modified T- and V-type compounds also indicated the possibility of achieving activity against highly glycopeptide-resistant enterococci by chemical derivatization of naturally occurring glycopeptides while maintaining unmodified the structure of the binding site. Recently, it has been found that the glycopeptide resistance in VanA enterococci is due to the replacement of target d -Ala- d -Ala by d -Ala- d -lactate depsipeptide in the peptidoglycan precursor. As glycopeptide 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 interact with membranes. The understanding of the mechanism of glycopeptide resistance in VanA enterococci, and the discovery of a selective procedure for the removal of amino acids 1 and 3 from natural glycopeptides also suggested new strategies which, based on molecular modeling studies, aim at obtaining glycopeptide-derived compounds suitably modified in their heptapeptide structure to allow simultaneous molecular interaction with both susceptible and resistant targets. As a preliminary approach, novel non-natural glycopeptides in which amino acids 1 and 3 are replaced by new amino acids have been prepared.