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.
Suree
Nuttee
N
Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095-1570, USA.
Yi
Sung Wook
SW
Thieu
William
W
Marohn
Melanie
M
Damoiseaux
Robert
R
Chan
Albert
A
Jung
Michael E
ME
Clubb
Robert T
RT
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