期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 14, 期 7, 页码 993-998出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.3c00187
关键词
Antimicrobial; antibacterial; DNA gyrase; topoisomerase; NBTI
Novel bacterial topoisomerase inhibitors (NBTIs) have been discovered to target clinically validated bacterial type II topoisomerases and effectively combat multidrug-resistant Gram-negative bacteria. The discovery of a series of NBTIs with a novel indane DNA binding moiety, as well as their interaction with Staphylococcus aureus DNA gyrase-DNA, has been reported. The lead compound 18c shows potent broad-spectrum activity against multidrug-resistant Gram-negative bacteria.
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.
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