Discovery and development of substituted thiadiazoles as inhibitors of Staphylococcus aureus Sortase A

Patrick M Wehrli; Ivana Uzelac; Thomas Olsson; Tomas Jacso; Daniel Tietze; Johan Gottfries

doi:10.1016/j.bmc.2019.115043

Discovery and development of substituted thiadiazoles as inhibitors of Staphylococcus aureus Sortase A

Bioorg Med Chem. 2019 Oct 1;27(19):115043. doi: 10.1016/j.bmc.2019.115043. Epub 2019 Aug 7.

Authors

Patrick M Wehrli¹, Ivana Uzelac², Thomas Olsson³, Tomas Jacso⁴, Daniel Tietze², Johan Gottfries¹

Affiliations

¹ Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden; Centre for Antibiotic Resistance Research (CARe) at University of Gothenburg, Gothenburg, Sweden.
² Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden.
³ Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden. Electronic address: thomas.olsson@chem.gu.se.
⁴ Structure & Biophysics, Discovery Sciences, AstraZeneca R&D, Sweden; Early Discovery, Department of Biology, Nuevolution AB, Denmark.

PMID: 31420255
DOI: 10.1016/j.bmc.2019.115043

Abstract

High-throughput screening of small-molecule libraries has led to the identification of thiadiazoles as a new class of inhibitors against Staphylococcus aureus sortase A (SrtA). N-(5-((4-nitrobenzyl)thio)-1,3,4-thiadiazol-2-yl)nicotinamide (IC₅₀ = 3.8 µM) was identified as a potent inhibitor of SrtA after synthetic modification of hit compounds. Additional ligands developed in this study displayed affinities in the low micromolar range without affecting bacterial growth in vitro. The study also suggest a new mode of action through covalent binding to the active site cysteine.

Keywords: Anti-virulence drugs; Antimicrobial resistance; Sortase A; SrtA inhibitors; Staphylococcus aureus.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aminoacyltransferases / chemistry
Aminoacyltransferases / metabolism*
Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / metabolism
Anti-Bacterial Agents / pharmacology*
Bacterial Proteins / chemistry
Bacterial Proteins / metabolism*
Catalytic Domain
Cysteine Endopeptidases / chemistry
Cysteine Endopeptidases / metabolism*
Cysteine Proteinase Inhibitors / chemical synthesis
Cysteine Proteinase Inhibitors / metabolism
Cysteine Proteinase Inhibitors / pharmacology*
Drug Discovery
Escherichia coli / drug effects
High-Throughput Screening Assays
Microbial Sensitivity Tests
Molecular Docking Simulation
Molecular Structure
Protein Binding
Staphylococcus aureus / drug effects
Staphylococcus aureus / enzymology*
Structure-Activity Relationship
Thiadiazoles / chemical synthesis
Thiadiazoles / metabolism
Thiadiazoles / pharmacology*

Substances

Anti-Bacterial Agents
Bacterial Proteins
Cysteine Proteinase Inhibitors
Thiadiazoles
Aminoacyltransferases
sortase A
Cysteine Endopeptidases