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

• Published in: European journal of medicinal chemistry Vol. 161; pp. 93 - 100
• Main Authors: Wójcik, Magdalena, Eleftheriadis, Nikolaos, Zwinderman, Martijn R.H., Dömling, Alexander S.S., Dekker, Frank J., Boersma, Ykelien L.
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.01.2019; Elsevier
• Subjects: Aminoacyltransferases - antagonists & inhibitors; Aminoacyltransferases - metabolism; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antivirulence; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - metabolism; Chemistry, Medicinal; Cysteine Endopeptidases - metabolism; Dose-Response Relationship, Drug; Drug Design; Drug Evaluation, Preclinical; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Inhibitor; Kinetics; Life Sciences & Biomedicine; Microbial Sensitivity Tests; Molecular Structure; Pharmacology & Pharmacy; Science & Technology; Sortase A; Streptococcus pyogenes; Streptococcus pyogenes - drug effects; Streptococcus pyogenes - enzymology; Structure-Activity Relationship; Substitution-oriented screening; Antivirulence; Sortase A; Streptococcus pyogenes; Inhibitor; Substitution-oriented screening; PATHOGENESIS; TARGET; PROTEINS; 15-LIPOXYGENASE-1
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.10.027

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 Kd 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. [Display omitted] •Sortase A is used as a target for the development of new antivirulence drugs.•A focused library of small, indole-based molecules was designed.•Substitution-oriented fragment screening was applied to find a potent inhibitor.•Molecular modeling was performed to propose binding of the inhibitor and the enzyme.