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New dual inhibitors of bacterial topoisomerases with broad-spectrum antibacterial activity and In vivo efficacy against vancomycin - intermediate Staphylococcus aureus [Elektronski vir]Durcik, Martina ...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.Source: Journal of medicinal chemistry [Elektronski vir]. - ISSN 1520-4804 (Vol. 66, iss. 6, 2023, str. 3968-3994)Type of material - e-article ; adult, seriousPublish date - 2023Language - englishCOBISS.SI-ID - 144333571
Author
Durcik, Martina |
Cotman, Andrej Emanuel |
Toplak, Žan |
Možina, Štefan, kemik |
Skok, Žiga, farmacevt |
Piras, Maria Vittoria |
Zidar, Nace |
Ilaš, Janez |
Zega, Anamarija |
Trontelj, Jurij |
Kikelj, Danijel |
Tomašič, Tihomir |
Peterlin-Mašič, Lucija
Topics
Farmacevtska kemija |
Bakterije |
Bakterijska rezistenca |
antibacterial activity |
bacteria |
inhibitors |
antibakterijsko delovanje |
zaviralci |
nanomolarni inhibitorji benzotiazola |
topoizomeraza IV
Author | Durcik, Martina ... |
Title | New dual inhibitors of bacterial topoisomerases with broad-spectrum antibacterial activity and In vivo efficacy against vancomycin - intermediate Staphylococcus aureus [Elektronski vir] |
Publication date | 2023-03-06 |
COBISS.SI-ID | 144333571 |
Publication version in repository | Publisher's version |
Publication licence | Creative Commons Attribution 4.0 International |
Embargo | Immediate publication for public |
Project(s) from which the publication was funded
Title | Acronym | Project ID | Funder |
---|---|---|---|
Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin | P1-0208-2022 |
Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije |
|
MTAvsAMR: novi večtarčni antibiotiki proti večkratno odpornim bakterijam | J1-3030-2021 |
Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije |
|
Razvoj novih zaviralcev bakterijskih topoizomeraz za boj proti odpornim infekcijam | J1-3031-2021 |
Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije |
|
Bacterial evolution of hypersensitivity and resistance against antimicrobial peptides | resistance evolution | 648364 |
European Commission |
Sofinanciranje znanstvenoraziskovalnega sodelovanja med Republiko Slovenijo in Madžarsko v letih 2021 in 2022 | BI-HU/19-20-008 | ||
European Gram Negative Antibacterial Engine | ENABLE | 115583 |
European Commission |
BB/J014524/1 | BB/J014524/1 |
Research Council UK |
|
Investigator Award | 110072/Z/15/Z |
Wellcome Trust |
|
BSRC, Institute Strategic Programme | BB/P012523/1 |
Research Council UK |
|
National Research Development and Innovation Office “Élvonal” Programme | KKP 126506 | ||
ELKH, Lendület Programme | LP-2017–10/2020 | ||
National Laboratory of Biotechnology | NKFIH-871-3/2020 | ||
National Laboratory of Biotechnology | 2022-2.1.1-NL-2022-00008 | ||
Ministry for Culture and Innovation, National Research, Development and Innovation Fund, New National Excellence Program | ÚNKP-22-4 | ||
Ministry for Culture and Innovation, National Research, Development and Innovation Fund, New National Excellence Program | ÚNKP-22-2 |
Files that belong to the publication
Link |
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https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c01905 |
https://repozitorij.uni-lj.si/IzpisGradiva.php?id=145096 |
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DRS, in which the journal is indexed
Database name | Field | Year |
---|
Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
---|---|
Durcik, Martina | 50490 |
Cotman, Andrej Emanuel | 37459 |
Toplak, Žan | 52375 |
Možina, Štefan, kemik | 36492 |
Skok, Žiga, farmacevt | 39202 |
Piras, Maria Vittoria | |
Zidar, Nace | 28905 |
Ilaš, Janez | 24400 |
Zega, Anamarija | 18633 |
Trontelj, Jurij | 23420 |
Kikelj, Danijel | 01463 |
Tomašič, Tihomir | 28334 |
Peterlin-Mašič, Lucija | 19317 |
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