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New dual ATP-competitive inhibitors of bacterial DNA gyrase and topoisomerase IV active against ESKAPE pathogensDurcik, Martina ...The rise in multidrug-resistant bacteria defines the need for identification of new antibacterial agents that are less prone to resistance acquisition. Compounds that simultaneously inhibit multiple ... bacterial targets are more likely to suppress the evolution of target-based resistance than monotargeting compounds. The structurally similar ATP binding sites of DNA gyrase and topoisomerase - offer an opportunity to accomplish this goal. Here we present the design and structure-activity relationship analysis of balanced, low nanomolar inhibitors of bacterial DNA gyrase and topoisomerase IV that show potent antibacterial activities against the ESKAPE pathogens. For inhibitor 31c, a crystal structure in complex with Staphylococcus aureus DNA gyrase B was obtained that confirms the mode of action of these compounds. The best inhibitor, 31h, does not show any in vitro cytotoxicity and has excellent potency against Gram-positive (MICs: range, 0.0078-0.0625 [micro]g/mL) and Gram-negative pathogens (MICs: range, 1-2 [micro]g/mL). Furthermore, 31h inhibits GyrB mutants that can develop resistance to other drugs. Based on these data, we expect that structural derivatives of 31h will represent a step toward clinically efficacious multitargeting antimicrobials that are not impacted by existing antimicrobial resistance.Source: European journal of medicinal chemistry. - ISSN 0223-5234 (Vol. 213, 2021, str. 1-22)Type of material - article, component part ; adult, seriousPublish date - 2021Language - englishCOBISS.SI-ID - 48579843
Author
Durcik, Martina |
Nyerges, Ákos |
Skok, Žiga, farmacevt |
Gramec, Darja, farmacevtka |
Trontelj, Jurij |
Zidar, Nace |
Ilaš, Janez |
Zega, Anamarija |
Kikelj, Danijel |
Peterlin-Mašič, Lucija |
Tomašič, Tihomir
Topics
Farmacevtska kemija |
Bakterijska rezistenca |
dual inhibitor |
DNA gyrase |
topoisomerase IV |
benzothiazole |
antibacterial |
slv |
zaviralci |
DNA giraze |
topoizimeraza IV |
antibakterijske učinkovine
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Author | Durcik, Martina ... |
Title | New dual ATP-competitive inhibitors of bacterial DNA gyrase and topoisomerase IV active against ESKAPE pathogens |
Publication date | 2021-03-28 |
COBISS.SI-ID | 48579843 |
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 |
---|---|---|---|
Nove protitumorne učinovine napetostno odvisnih kalijevih kanalov hEag1 in njihova validacija v limfomih | J1-9192-2018 |
Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije |
|
Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin | P1-0208-2015 |
Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije |
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Database name | Field | Year |
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Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
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Durcik, Martina | 50490 |
Nyerges, Ákos | ![]() |
Skok, Žiga, farmacevt | 39202 |
Gramec, Darja, farmacevtka | 35432 |
Trontelj, Jurij | 23420 |
Zidar, Nace | 28905 |
Ilaš, Janez | 24400 |
Zega, Anamarija | 18633 |
Kikelj, Danijel | 01463 |
Peterlin-Mašič, Lucija | 19317 |
Tomašič, Tihomir | 28334 |
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