Martina Durcik (Author), Andrej Emanuel Cotman (Author), Žan Toplak (Author), Štefan Možina (Author), Žiga Skok (Author), Maria Vittoria Piras (Author), Lucija Peterlin-Mašič (Author), Nace Zidar (Author), Janez Ilaš (Author), Anamarija Zega (Author), Jurij Trontelj (Author), Danijel Kikelj (Author), Tihomir Tomašić (Author)

Abstract

A new series of dual low nanomolar benzothiazole inhibitors of bacterial DNA gyrase and topoisomerase IV were developed. The resulting compounds show excellent broad-spectrum antibacterial activities against Gram-positive Enterococcus faecalis, Enterococcus faecium and multidrug resistant (MDR) Staphylococcus aureus strains [best compound minimal inhibitory concentrations (MICs): range, <0.03125–0.25 μg/mL] and against the Gram-negatives Acinetobacter baumannii and Klebsiella pneumoniae (best compound MICs: range, 1–4 μg/mL). Lead compound 7a was identified with favorable solubility and plasma protein binding, good metabolic stability, selectivity for bacterial topoisomerases, and no toxicity issues. The crystal structure of 7a in complex with Pseudomonas aeruginosa GyrB24 revealed its binding mode at the ATP-binding site. Expanded profiling of 7a and 7h showed potent antibacterial activity against over 100 MDR and non-MDR strains of A. baumannii and several other Gram-positive and Gram-negative strains. Ultimately, in vivo efficacy of 7a in a mouse model of vancomycin-intermediate S. aureus thigh infection was also demonstrated.

Keywords

antibacterial activity;bacteria;inhibitors;

Data

Language: English
Year of publishing:
Typology: 1.01 - Original Scientific Article
Organization: UL FFA - Faculty of Pharmacy
UDC: 615.015.8
COBISS: 144333571 Link will open in a new window
ISSN: 1520-4804
Views: 53
Downloads: 19
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Other data

Secondary language: Slovenian
Secondary keywords: antibakterijsko delovanje;zaviralci;nanomolarni inhibitorji benzotiazola;topoizomeraza IV;Farmacevtska kemija;Bakterije;Bakterijska rezistenca;
Type (COBISS): Article
Pages: str. 3968-3994
Volume: ǂVol. ǂ66
Issue: ǂiss. ǂ6
Chronology: 2023
DOI: 10.1021/acs.jmedchem.2c01905
ID: 18498164