Discovery and structure–activity relationship analysis of Staphylococcus aureus sortase A inhibitors
作者:Nuttee Suree、Sung Wook Yi、William Thieu、Melanie Marohn、Robert Damoiseaux、Albert Chan、Michael E. Jung、Robert T. Clubb
DOI:10.1016/j.bmc.2009.08.067
日期:2009.10
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 IC50 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. (C) 2009 Elsevier Ltd. All rights reserved.