Inhibition of MurA enzyme from Escherichia coli by flavonoids and their synthetic analogues

Frlan, Rok (author), Hrast, Martina (author), Gobec, Stanislav (author)

MurA catalyzes the first step of peptidoglycan (PG) biosynthesis and is a validated target for the development of new antimicrobial agents. In this study, a library of 49 plant flavonoids and their synthetic derivatives were evaluated for their inhibitory properties against MurA from Escherichia coli. The compounds were tested with and without preincubation and with the addition of DTT to understand the mechanism of inhibition. Thirteen compounds were identified as reversible, time-dependent inhibitors, with inhibition levels ranging from 480 nM to 57 μM, and ampelopsin as the most potent compound. To investigate the major pharmacophore elements responsible for the activity, 2D-QSAR and docking analyzes were performed. The results showed that the catechol moiety and an additional aromatic system were the most important features contributing to the activity of the compounds. However, most of the compounds did not show antibacterial activity against E. coli and Staphylococcus aureus strains, suggesting that their inhibitory activity against MurA may not be strong enough to induce antibacterial effects. Nevertheless, our results suggest that flavonoids are a promising starting point to develop new inhibitors of MurA and show great potential for further steps in drug development.

• Language: English
• Keywords: assays, flavonoids, inhibition, inhibitors, peptides, proteins
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2023
• Number of pages: Str. 33006-33016
• Numbering: Vol. 8, iss. 36
• PID: 20.500.12556/RUL-154069
• UDC: 547.972:615.015.8
• ISSN on article: 2470-1343
• DOI: 10.1021/acsomega.3c04813
• COBISS.SI-ID: 181848835
• Publication date in RUL: 23.01.2024

Record is a part of a journal

• Title: ACS omega
• Shortened title: ACS omega
• Publisher: American Chemical Society
• ISSN: 2470-1343
• COBISS.SI-ID: 525873945

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: testi, inhibicija, zaviralci, proteini, flavonoidi, bakterijska rezistenca, peptidi, beljakovine

Projects

• Funder: ARRS - Slovenian Research Agency
• Project number: P1-0208
• Name: Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin

• Funder: ARRS - Slovenian Research Agency
• Project number: J1-2484
• Name: Razvoj protibakterijskih učinkovin z delovanjem na validirane tarče v biosintezi peptidoglikana