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Anthranilic acid inhibitors of undecaprenyl pyrophosphate synthase (UppS), an essential enzyme for bacterial cell wall biosynthesis
ID Jukič, Marko (Author), ID Rožman, Kaja (Author), ID Sova, Matej (Author), ID Barreteau, Hélène (Author), ID Gobec, Stanislav (Author)

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Abstract
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 (dk_c)
Typology:1.01 - Original Scientific Article
Organization:FFA - Faculty of Pharmacy
Year:2019
Publication status in journal:Published
Article version:Publisher's version of article
Number of pages:9 str.
Numbering:Vol. 9, art. 3322
PID:20.500.12556/RUL-125360 This link opens in a new window
UDC:615.015.8
ISSN on article:1664-302X
DOI:10.3389/fmicb.2018.03322 This link opens in a new window
COBISS.SI-ID:4662385 This link opens in a new window
Publication date in RUL:12.03.2021
Views:379
Downloads:159
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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 This link opens in a new window

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 - Agencija za raziskovalno dejavnost Republike Slovenije
Project number:P1-0208
Name:Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin

Funder:Drugi - Drug financer ali več financerjev
Funding programme:Centre National de la Recherche Scientifique
Project number:7757
Name:Projet International de Rechercher Scientifique

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