A novel peptidoglycan cross-linking enzyme for a β-lactam-resistant transpeptidation pathway
A novel peptidoglycan cross-linking enzyme for a β-lactam-resistant transpeptidation pathway
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DOI：
10.1074/jbc.m507384200
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发表时间：
2005-11-18
影响因子：
4.8
通讯作者：
Arthur, M
中科院分区：
文献类型：
--
作者：
Mainardi, JL;Fourgeaud, M;Arthur, M
β-内酰胺类抗生素仍然是治疗严重感染最常用的药物。由于β-内酰胺环和细菌细胞壁前体的D-丙氨酰（4）-D-丙氨酸（5）末端之间的结构相似性，药物充当DD-转肽酶的自杀底物，DD-转肽酶催化细胞壁组装的最后交联步骤。在这里，我们表明，这种作用机制可以被一种新型的转肽酶击败，这种转肽酶首次通过反向遗传学在屎肠球菌的β-内酰胺耐药突变体中鉴定。酶Ldt（fm）在体外催化β-内酰胺不敏感LD转肽反应中肽聚糖亚基的交联。Ldt（fm）对四肽供体的L-赖氨酰（3）-D-丙氨酸（4）肽键的特异性解释了抗性，因为与DD转肽所需的五肽供体中的D-丙氨酰（4）-D-丙氨酸（5）相比，底物不模拟β-内酰胺。Ldt（fm）同源物在分类学上遥远的细菌中偶尔会遇到，这表明LD-转肽酶介导的耐药性可能出现在各种病原体中。
The beta-lactam antibiotics remain the most commonly used to treat severe infections. Because of structural similarity between the beta-lactam ring and the D-alanyl(4)-D-alanine(5) extremity of bacterial cell wall precursors, the drugs act as suicide substrates of the DD-transpeptidases that catalyze the last cross-linking step of cell wall assembly. Here, we show that this mechanism of action can be defeated by a novel type of transpeptidase identified for the first time by reverse genetics in a beta-lactam-resistant mutant of Enterococcus faecium. The enzyme, Ldt(fm), catalyzes in vitro the cross-linking of peptidoglycan subunits in a beta-lactam-insensitive LD-transpeptidation reaction. The specificity of Ldt(fm) for the L-lysyl(3)-D-alanine(4) peptide bond of tetrapeptide donors accounts for resistance because the substrate does not mimic beta-lactams in contrast to D-alanyl(4)-D-alanine(5) in the pentapeptide donors required for DD-transpeptidation. Ldt(fm) homologues are encountered sporadically among taxonomically distant bacteria, indicating that LD-transpeptidase-mediated resistance may emerge in various pathogens.