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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
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Identification of potential antivirulence agents by substitution-oriented screening for inhibitors of Streptococcus

Magdalena Wójcik1, Nikolaos Eleftheriadis2, Martijn R H Zwinderman1

  • 1University of Groningen, Groningen Research Institute of Pharmacy, Department of Chemical and Pharmaceutical Biology, Antonius Deusinglaan 1, 9713 AV, Groningen, the Netherlands.

European Journal of Medicinal Chemistry
|October 22, 2018
PubMed

Insights

Antimicrobial resistance is a growing global threat. Researchers identified a novel inhibitor targeting sortase A in Streptococcus pyogenes, offering a potential new strategy against bacterial infections.

Area of Science:

  • Microbiology
  • Drug Discovery
  • Biochemistry

Background:

  • Antimicrobial resistance (AMR) is a significant global health challenge, leading to ineffective treatments for bacterial infections.
  • Pathogenic bacteria like Streptococcus pyogenes utilize virulence factors, often attached via sortase enzymes, to cause disease.
  • Sortase enzymes are crucial for bacterial pathogenicity and represent a promising target for novel antimicrobial therapies.

Purpose of the Study:

  • To identify and characterize inhibitors of sortase A from Streptococcus pyogenes.
  • To explore the potential of sortase enzymes as therapeutic targets for developing new antivirulence strategies.

Main Methods:

  • Utilized the substitution-oriented fragment screening (SOS) approach to discover inhibitors.
  • Assessed the potency and specificity of identified inhibitors against Streptococcus pyogenes sortase A.
  • Determined inhibition constants (IC50) and dissociation constants (Kd) for the lead inhibitor.

Main Results:

  • Discovered a potent and specific inhibitor, designated C10, targeting sortase A from Streptococcus pyogenes.
  • Inhibitor C10 demonstrated high specificity for Streptococcus pyogenes sortase A.
  • Quantified inhibitor C10's efficacy with an IC50 of 10 μM and a Kd of 60 μM.

Conclusions:

  • The identified inhibitor C10 serves as a valuable starting point for further drug development.
  • Sortase enzymes hold significant potential as therapeutic targets for combating bacterial infections and addressing antimicrobial resistance.
Keywords:
AntivirulenceInhibitorSortase AStreptococcus pyogenesSubstitution-oriented screening

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