A Vancomycin Derivative with a Pyrophosphate‐Binding Group: A Strategy to Combat Vancomycin‐Resistant Bacteria

Abstract

AbstractVancomycin, the drug of last resort for Gram‐positive bacterial infections, has also been rendered ineffective by the emergence of resistance in such bacteria. To combat the threat of vancomycin‐resistant bacteria (VRB), we report the development of a dipicolyl–vancomycin conjugate (Dipi‐van), which leads to enhanced inhibition of cell‐wall biosynthesis in VRB and displays in vitro activity that is more than two orders of magnitude higher than that of vancomycin. Conjugation of the dipicolyl moiety, which is a zinc‐binding ligand, endowed the parent drug with the ability to bind to pyrophosphate groups of cell‐wall lipids while maintaining the inherent binding affinity for pentapeptide termini of cell‐wall precursors. Furthermore, no detectable resistance was observed after several serial passages, and the compound reduced the bacterial burden by a factor of 5 logs at 12 mg kg−1 in a murine model of VRB kidney infection. The findings presented in this report stress the potential of our strategy to combat VRB infections.