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

ABSTRACT: The rise of multidrug-resistant (MDR) Gram-negative bacteria is a major global health problem necessitating the discovery of new classes of antibiotics. Novel bacterial topoisomerase inhibitors (NBTIs) target the clinically validated bacterial type II topoisomerases with a distinct binding site and mechanism of action to fluoroquinolone antibiotics, thus avoiding cross-resistance to this drug class. Here we report the discovery of a series of NBTIs incorporating a novel indane DNA binding moiety. X-ray cocrystal structures of compounds 2 and 17a bound to Staphylococcus aureus DNA gyrase-DNA were determined, revealing specific interactions with the enzyme binding pocket at the GyrA dimer interface and a long-range electrostatic interaction between the basic amine in the

SUBMITTER: Cumming JG 

PROVIDER: S-EPMC10350941 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature