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

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

doi:10.3389/fmicb.2018.03322

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 μg/mL).

Highlights

The alarming increase in number of resistant bacterial strains is forcing academia and pharmaceutical companies into a hasten development of new antibacterial drugs
Every structure in the library was compared to the selection of PAINS structures defined in SMARTS format and removed from the database if found similar (Saubern et al, 2011; PAINS definitions in SMARTS format can be found in supporting info.)
The initial compound library was reduced to a library of approximately 6.5 million compounds and 3D conformer database prepared with omega2 fast protocol within LigandScout as detailed in the supporting information

Summary

Introduction

The alarming increase in number of resistant bacterial strains is forcing academia and pharmaceutical companies into a hasten development of new antibacterial drugs. Undecaprenyl pyrophosphate synthase is an essential cytoplasmic enzyme in the biosynthesis of peptidoglycan that catalyzes the formation of isoprenoid UPP (C55-PP) from FPP and IPP in Abbreviations: AUC, area under the curve; cpds, compounds; FPP, farnesyl pyrophosphate; GlcNAc-MurNAcpentapeptide, N-acetylglucosamine-N-acetylmuramyl-pentapeptide; IPP, isopentenyl pyrophosphate; MD, molecular dynamics; PMB, polymyxin B; ROC, receiver operating characteristic curve; SAR, structure-activity relationship; UPP, undecaprenyl pyrophosphate; UppS, undecaprenyl pyrophosphate synthase. Despite the many published crystal structures of apo enzyme (Ko et al, 2001) or enzyme co-crystalized with substrates (Chang et al, 2004) and inhibitors (Guo et al, 2007), there is still no registered drug targeting UppS (Jukic et al, 2016)

Methods

Results

Conclusion