Discovery and structure–activity relationship analysis of Staphylococcus aureus sortase A inhibitors

Model of the Staphylococcus aureus sortase enzyme bound to a small molecule. Methicillin resistant Staphylococcus aureus (MRSA) is a major health problem that has created a pressing need for new antibiotics. Compounds that inhibit the S. aureus SrtA sortase may function as potent anti-infective agen...

Full description

Saved in:
Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2009-10, Vol.17 (20), p.7174-7185
Main Authors: Suree, Nuttee, Yi, Sung Wook, Thieu, William, Marohn, Melanie, Damoiseaux, Robert, Chan, Albert, Jung, Michael E., Clubb, Robert T.
Format: Article
Language:English
Subjects:
Aminoacyltransferases - antagonists & inhibitors
Antibacterial agents
Antibiotic
Antibiotics. Antiinfectious agents. Antiparasitic agents
Bacterial Proteins - antagonists & inhibitors
Biological and medical sciences
Cysteine Endopeptidases
Drug Discovery
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Inhibitor
Medical sciences
Pharmacology. Drug treatments
Pyridazines - chemistry
Pyridazines - pharmacology
Sortase
SrtA
Staphylococcus aureus
Staphylococcus aureus - enzymology
Staphylococcus aureus - growth & development
Structure-Activity Relationship
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Model of the Staphylococcus aureus sortase enzyme bound to a small molecule. Methicillin resistant Staphylococcus aureus (MRSA) is a major health problem that has created a pressing need for new antibiotics. Compounds that inhibit the S. aureus SrtA sortase may function as potent anti-infective agents as this enzyme attaches virulence factors to the cell wall. Using high-throughput screening, we have identified several compounds that inhibit the enzymatic activity of the SrtA. A structure–activity relationship (SAR) analysis led to the identification of several pyridazinone and pyrazolethione analogs that inhibit SrtA with IC 50 values in the sub-micromolar range. Many of these molecules also inhibit the sortase enzyme from Bacillus anthracis suggesting that they may be generalized sortase inhibitors.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2009.08.067