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Discovery and Hit-to-Lead Optimization of Benzothiazole scaffold-based DNA gyrase inhibitors with potent activity against Acinetobacter baumannii and Pseudomonas aeruginosa [Elektronski vir]Cotman, Andrej Emanuel ...We have developed compounds with a promising activity against Acinetobacter baumannii and Pseudomonas aeruginosa, which are both on the WHO priority list of antibiotic-resistant bacteria. Starting ... from DNA gyrase inhibitor 1, we identified compound 27, featuring a 10-fold improved aqueous solubility, a 10-fold improved inhibition of topoisomerase IV from A. baumannii and P. aeruginosa, a 10-fold decreased inhibition of human topoisomerase IIα, and no cross-resistance to novobiocin. Cocrystal structures of 1 in complex with Escherichia coli GyrB24 and (S)-27 in complex with A. baumannii GyrB23 and P. aeruginosa GyrB24 revealed their binding to the ATP-binding pocket of the GyrB subunit. In further optimization steps, solubility, plasma free fraction, and other ADME properties of 27 were improved by fine-tuning of lipophilicity. In particular, analogs of 27 with retained anti-Gram-negative activity and improved plasma free fraction were identified. The series was found to be nongenotoxic, nonmutagenic, devoid of mitochondrial toxicity, and possessed no ion channel liabilities.Vir: Journal of medicinal chemistry [Elektronski vir]. - ISSN 1520-4804 (Vol. 66, no. 2, 2023, str. 1380-1425)Vrsta gradiva - e-članek ; neleposlovje za odrasleLeto - 2023Jezik - angleškiCOBISS.SI-ID - 138544899
Avtor
Cotman, Andrej Emanuel |
Durcik, Martina |
Benedetto Tiz, Davide |
Fulgheri, Federica |
Secci, Daniela |
Sterle, Maša |
Možina, Štefan, kemik |
Skok, Žiga, farmacevt |
Zidar, Nace |
Zega, Anamarija |
Ilaš, Janez |
Peterlin-Mašič, Lucija |
Tomašič, Tihomir |
Kikelj, Danijel
Teme
Topnost |
Genetika |
Bakterije |
Bakterijska rezistenca |
antibacterial activity |
bacteria |
genetics |
inhibitors |
solubility |
antibakterijsko delovanje |
zaviralci
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Avtor | Cotman, Andrej Emanuel ... |
Naslov | Discovery and Hit-to-Lead Optimization of Benzothiazole scaffold-based DNA gyrase inhibitors with potent activity against Acinetobacter baumannii and Pseudomonas aeruginosa [Elektronski vir] |
Datum objave | 2023-01-26 |
COBISS.SI-ID | 138544899 |
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 |
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Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije |
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MTAvsAMR: novi večtarčni antibiotiki proti večkratno odpornim bakterijam | J1-3030-2021 |
Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije |
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Razvoj novih zaviralcev bakterijskih topoizomeraz za boj proti odpornim infekcijam | J1-3031-2021 |
Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije |
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European Gram Negative Antibacterial Engine | ENABLE | 115583 |
European Commission |
BB/J014524/1 | BB/J014524/1 |
Research Council UK |
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BSRC, Institute Strategic Programme | BB/P012523/1 |
Research Council UK |
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Investigator Award | 110072/Z/15/Z |
Wellcome Trust |
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Baze podatkov, v katerih je revija indeksirana
Ime baze podatkov | Področje | Leto |
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Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
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Cotman, Andrej Emanuel | 37459 |
Durcik, Martina | 50490 |
Benedetto Tiz, Davide | 57300 |
Fulgheri, Federica | ![]() |
Secci, Daniela | 58611 |
Sterle, Maša | 53583 |
Možina, Štefan, kemik | 36492 |
Skok, Žiga, farmacevt | 39202 |
Zidar, Nace | 28905 |
Zega, Anamarija | 18633 |
Ilaš, Janez | 24400 |
Peterlin-Mašič, Lucija | 19317 |
Tomašič, Tihomir | 28334 |
Kikelj, Danijel | 01463 |
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