1,3-Dioxane-Linked Novel Bacterial Topoisomerase Inhibitors: Expanding Structural Diversity and the Antibacterial Spectrum

Abstract

Antibacterial resistance continues its devastation of available therapies. Novel bacterial topoisomerase inhibitors (NBTIs) offer one solution to this critical issue. Two series of amine NBTIs bearing tricyclic DNA-binding moieties as well as amide NBTIs with a bicyclic DNA-binding moiety were synthesized and evaluated against methicillin-resistant Staphylococcus aureus (MRSA). Additionally, these compounds and a series of bicyclic amine analogues displayed high activity against susceptible and drug-resistant Neisseria gonorrhoeae, expanding the spectrum of these dioxane-linked NBTIs.

Interactions between Gepotidacin and Escherichia coli Gyrase and Topoisomerase IV: Genetic and Biochemical Evidence for Well-Balanced Dual-Targeting

“…Although interactions between other novel bacterial topoisomerase inhibitors and WT gyrase and topoisomerase IV have been reported, − the mechanisms underlying resistance to these compounds and to gepotidacin have yet to be explored. The studies presented here show that simultaneous mutations in both GyrA P35 and ParC D79 are required for a decreased susceptibility to gepotidacin in E.…”

“…A previous study that characterized the effects of gepotidacin on S. aureus gyrase found that the compound shares many mechanistic features with earlier preclinical candidate novel bacterial topoisomerase inhibitors. ,, However, virtually nothing is known regarding the actions of gepotidacin on topoisomerase IV. ,− Because of the clinical promise of gepotidacin against urinary tract infections, it is important to characterize how this compound affects the activities of both gyrase and topoisomerase IV in E. coli.…”

“…Like the fluoroquinolones, gepotidacin and other novel bacterial topoisomerase inhibitors (NBTIs) stabilize the cleavage complex ,− and inhibit overall enzyme activity. ,− However, in contrast to drugs like ciprofloxacin, gepotidacin and other NBTIs interact with different residues on gyrase and topoisomerase IV ,,− and induce enzyme-mediated single-stranded, as opposed to double-stranded, DNA breaks. − Although two fluoroquinolone molecules bind in the cleavage complex, inserting at the sites of DNA cleavage on both strands of the double-helix, ,,,,, like other NBTIs, a single gepotidacin molecule binds midway between the two scissile DNA bonds in a pocket between the two A subunits of the bacterial type II enzymes. ,,,− …”