Telavancin, a multifunctional lipoglycopeptide, disrupts both cell wall synthesis and cell membrane integrity in methicillin-resistant Staphylococcus aureus
Telavancin, a multifunctional lipoglycopeptide, disrupts both cell wall synthesis and cell membrane integrity in methicillin-resistant Staphylococcus aureus
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DOI：
10.1128/aac.49.3.1127-1134.2005
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发表时间：
2005-03-01
影响因子：
4.9
通讯作者：
Humphrey, PP
中科院分区：
文献类型：
--
作者：
Higgins, DL;Chang, R;Humphrey, PP
多重耐药革兰氏阳性菌的出现和传播是一个严重的临床问题。特拉万星是一种新型脂糖肽类抗生素，对临床相关的革兰氏阳性病原体具有快速的体外杀菌活性。在这里，我们证明特拉万星的抗菌活性来自至少两种机制。如用万古霉素所观察到的，特拉万星以底物依赖性方式抑制晚期肽聚糖生物合成并结合细胞壁，就像它以高亲和力结合脂质II替代三肽N，N '-二乙酰基-L-赖氨酰-D-丙氨酰-D-丙氨酸一样。特拉万星也扰乱细菌细胞膜电位和渗透性。在耐甲氧西林金黄色葡萄球菌中，特拉万星引起质膜快速的浓度依赖性去极化，通透性增加，以及细胞ATP和K+的泄漏。这些变化的时间与细菌活力的快速、浓度依赖性丧失相关，表明特拉万星的早期杀菌活性是由细胞膜电位的耗散和膜通透性的增加引起的。结合和细胞分级分离研究提供了特拉万星与细菌细胞膜相互作用的直接证据;相对于万古霉素，观察到与细菌细胞壁和细胞膜的更强的结合相互作用。我们认为，这种多功能的作用机制赋予有利的抗菌性能。
The emergence and spread of multidrug-resistant gram-positive bacteria represent a serious clinical problem. Telavancin is a novel lipoglycopeptide antibiotic that possesses rapid in vitro bactericidal activity against a broad spectrum of clinically relevant gram-positive pathogens. Here we demonstrate that telavancin's antibacterial activity derives from at least two mechanisms. As observed with vancomycin, telavancin inhibited late-stage peptidoglycan biosynthesis in a substrate-dependent fashion and bound the cell wall, as it did the lipid II surrogate tripeptide N,N'-diacetyl-L-lysinyl-D-alanyl-D-alanine, with high affinity. Telavancin also perturbed bacterial cell membrane potential and permeability. In methicillin-resistant Staphylococcus aureus, telavancin caused rapid, concentration-dependent depolarization of the plasma membrane, increases in permeability, and leakage of cellular ATP and K+. The timing of these changes correlated with rapid, concentration-dependent loss of bacterial viability, suggesting that the early bactericidal activity of telavancin results from dissipation of cell membrane potential and an increase in membrane permeability. Binding and cell fractionation studies provided direct evidence for an interaction of telavancin with the bacterial cell membrane; stronger binding interactions were observed with the bacterial cell wall and cell membrane relative to vancomycin. We suggest that this multifunctional mechanism of action confers advantageous antibacterial properties.