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

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

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).

• Jezik: Angleški jezik
• Ključne besede: UppS, inhibitors, cell-wall, pharmacophore model, antibacterial agents, undecaprenyl pyrophosphate synthase
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2019
• Št. strani: 9 str.
• Številčenje: Vol. 9, art. 3322
• PID: 20.500.12556/RUL-125360
• UDK: 615.015.8
• ISSN pri članku: 1664-302X
• DOI: 10.3389/fmicb.2018.03322
• COBISS.SI-ID: 4662385
• Datum objave v RUL: 12.03.2021

Gradivo je del revije

• Naslov: Frontiers in microbiology
• Skrajšan naslov: Front. microbiol.
• Založnik: Frontiers Research Foundation
• ISSN: 1664-302X
• COBISS.SI-ID: 4146296

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.
• Začetek licenciranja: 12.03.2021

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: bakterijska rezistenca, celična stena, farmakomorfni model

Projekti

• Financer: ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
• Številka projekta: P1-0208
• Naslov: Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin

• Financer: Drugi - Drug financer ali več financerjev
• Program financ.: Centre National de la Recherche Scientifique
• Številka projekta: 7757
• Naslov: Projet International de Rechercher Scientifique