Identification of potential antivirulence agents by substitution-oriented screening for inhibitors of Streptococcus pyogenes sortase A

Magdalena Wójcik; Nikolaos Eleftheriadis; Martijn R H Zwinderman; Alexander S S Dömling; Frank J Dekker; Ykelien L Boersma

doi:10.1016/j.ejmech.2018.10.027

Identification of potential antivirulence agents by substitution-oriented screening for inhibitors of Streptococcus pyogenes sortase A

Eur J Med Chem. 2019 Jan 1:161:93-100. doi: 10.1016/j.ejmech.2018.10.027. Epub 2018 Oct 15.

Authors

Magdalena Wójcik¹, Nikolaos Eleftheriadis², Martijn R H Zwinderman³, Alexander S S Dömling⁴, Frank J Dekker⁵, Ykelien L Boersma⁶

Affiliations

¹ University of Groningen, Groningen Research Institute of Pharmacy, Department of Chemical and Pharmaceutical Biology, Antonius Deusinglaan 1, 9713 AV, Groningen, the Netherlands. Electronic address: m.wojcik@rug.nl.
² University of Groningen, Groningen Research Institute of Pharmacy, Department of Chemical and Pharmaceutical Biology, Antonius Deusinglaan 1, 9713 AV, Groningen, the Netherlands; University of Groningen, Molecular Microscopy Research Group, Zernike Institute for Advanced Materials, Nijenborgh 4, 9747 AG, Groningen, the Netherlands. Electronic address: n.eleftheriadis@rug.nl.
³ University of Groningen, Groningen Research Institute of Pharmacy, Department of Chemical and Pharmaceutical Biology, Antonius Deusinglaan 1, 9713 AV, Groningen, the Netherlands. Electronic address: r.h.zwinderman@rug.nl.
⁴ University of Groningen, Groningen Research Institute of Pharmacy, Department of Drug Design, Antonius Deusinglaan 1, 9713 AV, Groningen, the Netherlands. Electronic address: a.s.s.domling@rug.nl.
⁵ University of Groningen, Groningen Research Institute of Pharmacy, Department of Chemical and Pharmaceutical Biology, Antonius Deusinglaan 1, 9713 AV, Groningen, the Netherlands. Electronic address: f.j.dekker@rug.nl.
⁶ University of Groningen, Groningen Research Institute of Pharmacy, Department of Chemical and Pharmaceutical Biology, Antonius Deusinglaan 1, 9713 AV, Groningen, the Netherlands. Electronic address: y.l.boersma@rug.nl.

PMID: 30343193
DOI: 10.1016/j.ejmech.2018.10.027

Abstract

Antimicrobial resistance resulting in ineffective treatment of infectious diseases is an increasing global problem, particularly in infections with pathogenic bacteria. In some bacteria, such as Streptococcus pyogenes, the pathogenicity is strongly linked to the attachment of virulence factors. Their attachment to the cellular membrane is a transpeptidation reaction, catalyzed by sortase enzymes. As such, sortases pose an interesting target for the development of new antivirulence strategies that could yield novel antimicrobial drugs. Using the substitution-oriented fragment screening (SOS) approach, we discovered a potent and specific inhibitor (C10) of sortase A from S. pyogenes. The inhibitor C10 showed high specificity towards S. pyogenes sortase A, with an IC₅₀ value of 10 μM and a K_d of 60 μM. We envision that this inhibitor could be employed as a starting point for further exploration of sortase's potential as therapeutic target for antimicrobial drug development.

Keywords: Antivirulence; Inhibitor; Sortase A; Streptococcus pyogenes; Substitution-oriented screening.

MeSH terms

Aminoacyltransferases / antagonists & inhibitors*
Aminoacyltransferases / metabolism
Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Bacterial Proteins / antagonists & inhibitors*
Bacterial Proteins / metabolism
Cysteine Endopeptidases / metabolism
Dose-Response Relationship, Drug
Drug Design
Drug Evaluation, Preclinical
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Kinetics
Microbial Sensitivity Tests
Molecular Structure
Streptococcus pyogenes / drug effects*
Streptococcus pyogenes / enzymology
Structure-Activity Relationship

Substances

Anti-Bacterial Agents
Bacterial Proteins
Enzyme Inhibitors
Aminoacyltransferases
sortase A
Cysteine Endopeptidases