Andrej Emanuel Cotman (Avtor), Martina Durcik (Avtor), Davide Benedetto Tiz (Avtor), Federica Fulgheri (Avtor), Maša Sterle (Avtor), Štefan Možina (Avtor), Danijel Kikelj (Avtor), Žiga Skok (Avtor), Nace Zidar (Avtor), Anamarija Zega (Avtor), Janez Ilaš (Avtor), Lucija Peterlin-Mašič (Avtor), Tihomir Tomašić (Avtor)

Povzetek

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.

Ključne besede

antibacterial activity;bacteria;genetics;inhibitors;solubility;

Podatki

Jezik: Angleški jezik
Leto izida:
Tipologija: 1.01 - Izvirni znanstveni članek
Organizacija: UL FFA - Fakulteta za farmacijo
UDK: 615.015.8
COBISS: 138544899 Povezava se bo odprla v novem oknu
ISSN: 1520-4804
Št. ogledov: 74
Št. prenosov: 36
Ocena: 0 (0 glasov)
Metapodatki: JSON JSON-RDF JSON-LD TURTLE N-TRIPLES XML RDFA MICRODATA DC-XML DC-RDF RDF

Ostali podatki

Sekundarni jezik: Slovenski jezik
Sekundarne ključne besede: antibakterijsko delovanje;zaviralci;Topnost;Genetika;Bakterije;Bakterijska rezistenca;
Vrsta dela (COBISS): Članek v reviji
Konec prepovedi (OpenAIRE): 2024-01-12
Strani: <v tisku>
Letnik: ǂVol. ǂ
Zvezek: ǂno. ǂ
Čas izdaje: 2023
DOI: 10.1021/acs.jmedchem.2c01597
ID: 18003288