Structurally optimized potent dual-targeting NBTI antibacterials with an enhanced bifurcated halogen-bonding propensityKokot, Maja (Avtor) Weiss, Matjaž (Avtor) Zdovc, Irena (Avtor) Hrast Rambaher, Martina (Avtor) Anderluh, Marko (Avtor) Minovski, Nikola (Avtor) NBTIsDNA gyrasetopoisomerase IVbifurcated halogen bondsdual targetingWe designed and synthesized an optimized library of novel bacterial topoisomerase inhibitors with p-halogenated phenyl right-hand side fragments and significantly enhanced and balanced dual-targeted DNA gyrase and topoisomerase IV activities of Staphylococcus aureus and Escherichia coli. By increasing the electron-withdrawing properties of the p-halogenated phenyl right-hand side fragment and maintaining a similar lipophilicity and size, an increased potency was achieved, indicating that the antibacterial activities of this series of novel bacterial topoisomerase inhibitors against all target enzymes are determined by halogen-bonding rather than van der Waals interactions. They show nanomolar enzyme inhibitory and whole-cell antibacterial activities against S. aureus and methicillin-resistant S. aureus (MRSA) strains. However, due to the relatively high substrate specificity for the bacterial efflux pumps, they tend to be less potent against E. coli and other Gram-negative pathogens.20212022-09-29 12:56:15Članek v reviji141453sl