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

Marko Jukič (Author), Kaja Rožman (Author), Matej Sova (Author), Hélene Barreteau (Author), Stanislav Gobec (Author)

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 microM) and good antibacterial activity against E. coli BW25113 tolC strain (MIC = 0.5 %micro/mL).

Keywords

UppS;inhibitors;cell-wall;pharmacophore model;antibacterial agents;undecaprenyl pyrophosphate synthase;

Data

Language:	English
Year of publishing:	2019
Typology:	1.01 - Original Scientific Article
Organization:	UL FFA - Faculty of Pharmacy
Publisher:	Frontiers Media
UDC:	615.015.8
COBISS:	4662385
ISSN:	1664-302X
Views:	349
Downloads:	151
Average score:	0 (0 votes)
Metadata:

Other data

Secondary language:	Slovenian
Secondary keywords:	Bakterijska rezistenca;
Type (COBISS):	Article
Pages:	str. 1-9
Issue:	ǂVol. ǂ9
Chronology:	14. Jan. 2019
DOI:	10.3389/fmicb.2018.03322
ID:	12639641