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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.Vir: European journal of medicinal chemistry. - ISSN 0223-5234 (Vol. 213, 2021, str. 1-22)Vrsta gradiva - članek, sestavni del ; neleposlovje za odrasleLeto - 2021Jezik - angleškiCOBISS.SI-ID - 48579843
Avtor
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
Teme
Farmacevtska kemija |
Bakterijska rezistenca |
dual inhibitor |
DNA gyrase |
topoisomerase IV |
benzothiazole |
antibacterial |
slv |
zaviralci |
DNA giraze |
topoizimeraza IV |
antibakterijske učinkovine
Avtor | Durcik, Martina ... |
Naslov | New dual ATP-competitive inhibitors of bacterial DNA gyrase and topoisomerase IV active against ESKAPE pathogens |
Datum objave | 2021-03-28 |
COBISS.SI-ID | 48579843 |
Verzija objave v repozitoriju | Založnikova različica |
Licenca objave v repozitoriju | Creative Commons Priznanje avtorstva 4.0 Mednarodna |
Embargo | Takojšnja javna objava |
Projekti, iz katerih je bila financirana objava
Naziv | Akronim | Številka projekta | Financer |
---|---|---|---|
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 |
Datoteke, ki spadajo k objavi
Povezava |
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https://www.sciencedirect.com/science/article/pii/S0223523421000490#! |
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Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
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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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