AUTHOR=Jukič Marko , Rožman Kaja , Sova Matej , Barreteau Hélène , Gobec Stanislav 

TITLE=Anthranilic Acid Inhibitors of Undecaprenyl Pyrophosphate Synthase (UppS), an Essential Enzyme for Bacterial Cell Wall Biosynthesis

JOURNAL=Frontiers in Microbiology

VOLUME=9

YEAR=2019

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2018.03322

DOI=10.3389/fmicb.2018.03322

ISSN=1664-302X

ABSTRACT=<p>We report the successful implementation of virtual screening in the discovery of new inhibitors of undecaprenyl pyrophosphate synthase (UppS) from <italic>Escherichia coli.</italic> 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 <italic>cis</italic>-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 <bold>BPH-629</bold> 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 <bold>2</bold> displayed high inhibitory potency (IC<sub>50</sub> = 25 μM) and good antibacterial activity against <italic>E. coli</italic> BW25113 Δ<italic>tolC</italic> strain (MIC = 0.5 μg/mL).</p>