Discovery and structure-activity relationship analysis of Staphylococcus aureus sortase A inhibitors.
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.
Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095-1570, USA.
Nuttee
N
Suree
Sung Wook
SW
Yi
William
W
Thieu
Melanie
M
Marohn
Robert
R
Damoiseaux
Albert
A
Chan
Michael E
ME
Jung
Robert T
RT
Clubb
D019881:Aminoacyltransferases / Q000037:antagonists & inhibitors*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D003546:Cysteine Endopeptidases; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011724:Pyridazines / Q000737:chemistry* / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000201:enzymology* / Q000254:growth & development; D013329:Structure-Activity Relationship
D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D011724:Pyridazines; D019881:Aminoacyltransferases; C120542:sortase A; D003546:Cysteine Endopeptidases