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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 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.

SUBMITTER: Kokot M

PROVIDER: S-EPMC8436411 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Bifurcated Halogen Bonding Involving Two Rhodium(I) Centers as an Integrated σ-Hole Acceptor.

Project description:The complexes [RhX(COD)]2 (X = Cl, Br; COD = 1,5-cyclooctadiene) form cocrystals with σ-hole iodine donors. X-ray diffraction studies and extensive theoretical considerations indicate that the d z 2-orbitals of two positively charged rhodium(I) centers provide sufficient nucleophilicity to form a three-center halogen bond (XB) with the σ-hole donors. The two metal centers function as an integrated XB acceptor, providing assembly via a metal-involving XB.

| S-EPMC8395620 | biostudies-literature

Potent DNA gyrase inhibitors bind asymmetrically to their target using symmetrical bifurcated halogen bonds.

Project description:Novel bacterial type II topoisomerase inhibitors (NBTIs) stabilize single-strand DNA cleavage breaks by DNA gyrase but their exact mechanism of action has remained hypothetical until now. We have designed a small library of NBTIs with an improved DNA gyrase-binding moiety resulting in low nanomolar inhibition and very potent antibacterial activity. They stabilize single-stranded cleavage complexes and, importantly, we have obtained the crystal structure where an NBTI binds gyrase-DNA in a single conformation lacking apparent static disorder. This directly proves the previously postulated NBTI mechanism of action and shows that they stabilize single-strand cleavage through asymmetric intercalation with a shift of the scissile phosphate. This crystal stucture shows that the chlorine forms a halogen bond with the backbone carbonyls of the two symmetry-related Ala68 residues. To the best of our knowledge, such a so-called symmetrical bifurcated halogen bond has not been identified in a biological system until now.

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Embracing the Diversity of Halogen Bonding Motifs in Fragment-Based Drug Discovery-Construction of a Diversity-Optimized Halogen-Enriched Fragment Library.

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| S-EPMC8596797 | biostudies-literature

Activation of a Metal-Halogen Bond by Halogen Bonding.

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| S-EPMC5585772 | biostudies-literature

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