Anthranilic acid inhibitors of undecaprenyl pyrophosphate synthase (UppS), an essential enzyme for bacterial cell wall biosynthesis

Jukič, Marko (author), Rožman, Kaja (author), Sova, Matej (author), Barreteau, Hélène (author), Gobec, Stanislav (author)

We report the successful implementation of virtual screening in the discovery of new inhibitors of undecaprenyl pyrophosphate synthase (UppS) from Escherichia coli. UppS is an essential enzyme in the biosynthesis of bacterial cell wall. It catalyzes the condensation of farnesyl pyrophosphate (FPP) with eight consecutive isopentenyl pyrophosphate units (IPP), in which new cis-double bonds are formed, to generate undecaprenyl pyrophosphate. The latter serves as a lipid carrier for peptidoglycan synthesis, thus representing an important target in the antibacterial drug design. A pharmacophore model was designed on a known bisphosphonate BPH-629 and used to prepare an enriched compound library that was further docked into UppS conformational ensemble generated by molecular dynamics experiment. The docking resulted in three anthranilic acid derivatives with promising inhibitory activity against UppS. Compound 2 displayed high inhibitory potency (IC50 = 25 μM) and good antibacterial activity against E. coli BW25113 ΔtolC strain (MIC = 0.5 μ/mL).

• Language: English
• Keywords: UppS, inhibitors, cell-wall, pharmacophore model, antibacterial agents, undecaprenyl pyrophosphate synthase
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2019
• Number of pages: 9 str.
• Numbering: Vol. 9, art. 3322
• PID: 20.500.12556/RUL-125360
• UDC: 615.015.8
• ISSN on article: 1664-302X
• DOI: 10.3389/fmicb.2018.03322
• COBISS.SI-ID: 4662385
• Publication date in RUL: 12.03.2021

Record is a part of a journal

• Title: Frontiers in microbiology
• Shortened title: Front. microbiol.
• Publisher: Frontiers Research Foundation
• ISSN: 1664-302X
• COBISS.SI-ID: 4146296

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.
• Licensing start date: 12.03.2021

Secondary language

• Language: Slovenian
• Keywords: bakterijska rezistenca, celična stena, farmakomorfni model

Projects

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

• Funder: Other - Other funder or multiple funders
• Funding programme: Centre National de la Recherche Scientifique
• Project number: 7757
• Name: Projet International de Rechercher Scientifique