Discovery of a Series of Indane-Containing NBTIs with Activity against Multidrug-Resistant Gram-Negative Pathogens

Therise of multidrug-resistant (MDR) Gram-negative bacteria isa major global health problem necessitating the discovery of new classesof antibiotics. Novel bacterial topoisomerase inhibitors (NBTIs) targetthe clinically validated bacterial type II topoisomerases with a distinctbinding site and mechanism of action to fluoroquinolone antibiotics,thus avoiding cross-resistance to this drug class. Here we reportthe discovery of a series of NBTIs incorporating a novel indane DNAbinding moiety. X-ray cocrystal structures of compounds 2 and 17a bound to Staphylococcus aureus DNA gyrase-DNA were determined, revealing specific interactionswith the enzyme binding pocket at the GyrA dimer interface and a long-rangeelectrostatic interaction between the basic amine in the linker andthe carboxylate of Asp83. Exploration of the structure-activityrelationship within the series led to the identification of lead compound 18c, which showed potent broad-spectrum activity against apanel of MDR Gram-negative bacteria.