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

被引：85

作者：

Suree, Nuttee ^{[1
,2
]}

Yi, Sung Wook ^{[1
]}

Thieu, William ^{[1
]}

Marohn, Melanie ^{[1
]}

Damoiseaux, Robert

Chan, Albert ^{[1
,2
]}

Jung, Michael E. ^{[1
]}

Clubb, Robert T. ^{[1
,2
,3
]}

机构：

[1] Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA

[2] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA

[3] Univ Calif Los Angeles, Inst Genom & Prote, Dept Energy, Los Angeles, CA 90095 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2009年 / 17卷 / 20期

关键词：

Antibiotic; Staphylococcus aureus; Sortase; SrtA; Inhibitor; GRAM-POSITIVE BACTERIA; PROTEIN ANCHORING TRANSPEPTIDASE; CELL-WALL ENVELOPE; SURFACE-PROTEINS; SRTA GENE; LISTERIA-MONOCYTOGENES; BACILLUS-ANTHRACIS; SUBSTRATE COMPLEX; DRUG DISCOVERY; SORTING SIGNAL;

D O I：

10.1016/j.bmc.2009.08.067

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：7174 / 7185

页数：12

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