Structurally Optimized Potent Dual-Targeting NBTI Antibacterials with an Enhanced Bifurcated Halogen-Bonding Propensity

Abstract

We designed and synthesized an optimized library of novel bacterial topoisomerase inhibitors with <i>p</i>-halogenated phenyl right-hand side fragments and significantly enhanced and balanced dual-targeted DNA gyrase and topoisomerase IV activities of <i>Staphylococcus aureus</i> and <i>Escherichia coli</i>. By increasing the electron-withdrawing properties of the <i>p</i>-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 <i>S. aureus</i> and methicillin-resistant <i>S. aureus</i> (MRSA) strains. However, due to the relatively high substrate specificity for the bacterial efflux pumps, they tend to be less potent against <i>E. coli</i> and other Gram-negative pathogens.