New dual inhibitors of bacterial topoisomerases with broad-spectrum antibacterial activity and in vivo efficacy against vancomycin-intermediate Staphylococcus aureus

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

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.

• Language: English
• Keywords: antibacterial activity, bacteria, inhibitors, genetics, inhibition, peptides and proteins
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2023
• Number of pages: Str. 3968-3994
• Numbering: Vol. 66, iss. 6
• PID: 20.500.12556/RUL-145096
• UDC: 615.015.8
• ISSN on article: 1520-4804
• DOI: 10.1021/acs.jmedchem.2c01905
• COBISS.SI-ID: 144333571
• Publication date in RUL: 05.04.2023

Record is a part of a journal

• Title: Journal of medicinal chemistry
• Shortened title: J. med. chem.
• Publisher: American Chemical Society
• ISSN: 1520-4804
• COBISS.SI-ID: 512806681

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: antibakterijsko delovanje, zaviralci, nanomolarni inhibitorji benzotiazola, topoizomeraza IV, farmacevtska kemija, bakterije, bakterijska rezistenca