Structural Variations of the Cell Wall Precursor Lipid II and Their Influence on Binding and Activity of the Lipoglycopeptide Antibiotic Oritavancin
Structural Variations of the Cell Wall Precursor Lipid II and Their Influence on Binding and Activity of the Lipoglycopeptide Antibiotic Oritavancin
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DOI：
10.1128/aac.02663-14
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发表时间：
2015-02-01
影响因子：
4.9
通讯作者：
Schneider, Tanja
中科院分区：
文献类型：
--
作者：
Muench, Daniela;Engels, Ina;Schneider, Tanja
奥利万星是糖肽类抗生素氯伊瑞霉素的半合成衍生物，具有抗革兰氏阳性病原体（包括耐万古霉素的葡萄球菌和肠球菌）的活性。与万古霉素相比，奥利万星的特征在于存在两个额外的残基，疏水性4 '-氯联苯甲基部分和4-表-万古胺取代基，其也存在于氯伊瑞霉素中。在这里，我们表明，奥利万星和它的des-N-甲基亮氨酰变体（解吸万星）有效地抑制脂质I和脂质II消耗肽聚糖的生物合成反应在体外。与万古霉素相反，奥利万星与细胞壁前体脂质II的结合亲和力似乎除了D-Ala-D-Ala末端之外还涉及脂质II分子的其他物种特异性结合位点，即，在脂质II茎肽的位置2处的交联桥和D-异谷氨酰胺，两者都是许多革兰氏阳性病原体的特征，包括葡萄球菌和肠球菌。使用纯化的脂质II和修饰的脂质II变体，我们研究了这些修饰对奥利万星结合的影响，并将其与万古霉素、氯伊瑞霉素和去奥利万星的影响进行了比较。结合参数的分析表明，奥利万星与肽聚糖前体的额外分子内相互作用似乎补偿了万古霉素耐药菌株中关键氢键的损失，从而增强了结合亲和力。增强以前的研究结果，我们表明，酰胺化的脂质II茎肽主要占奥利万星的结合增加的修改后的中间体结束在D-丙氨酸-D-乳糖。证实我们的结论，我们进一步提供了生化证据的现象的拮抗作用的mecA和vanA耐药决定簇的金黄色葡萄球菌，从而部分解释了低频率的耐甲氧西林的S。金黄色葡萄球菌（MRSA）获得高水平的万古霉素耐药性。
Oritavancin is a semisynthetic derivative of the glycopeptide antibiotic chloroeremomycin with activity against Gram-positive pathogens, including vancomycin-resistant staphylococci and enterococci. Compared to vancomycin, oritavancin is characterized by the presence of two additional residues, a hydrophobic 4'-chlorobiphenyl methyl moiety and a 4-epi-vancosamine substituent, which is also present in chloroeremomycin. Here, we show that oritavancin and its des-N-methylleucyl variant (desoritavancin) effectively inhibit lipid I-and lipid II-consuming peptidoglycan biosynthesis reactions in vitro. In contrast to that for vancomycin, the binding affinity of oritavancin to the cell wall precursor lipid II appears to involve, in addition to the D-Ala-D- Ala terminus, other species-specific binding sites of the lipid II molecule, i.e., the crossbridge and D-isoglutamine in position 2 of the lipid II stem peptide, both characteristic for a number of Gram-positive pathogens, including staphylococci and enterococci. Using purified lipid II and modified lipid II variants, we studied the impact of these modifications on the binding of oritavancin and compared it to those of vancomycin, chloroeremomycin, and des-oritavancin. Analysis of the binding parameters revealed that additional intramolecular interactions of oritavancin with the peptidoglycan precursor appear to compensate for the loss of a crucial hydrogen bond in vancomycin-resistant strains, resulting in enhanced binding affinity. Augmenting previous findings, we show that amidation of the lipid II stem peptide predominantly accounts for the increased binding of oritavancin to the modified intermediates ending in D-Ala-D-Lac. Corroborating our conclusions, we further provide biochemical evidence for the phenomenon of the antagonistic effects of mecA and vanA resistance determinants in Staphylococcus aureus, thus partially explaining the low frequency of methicillin-resistant S. aureus (MRSA) acquiring high-level vancomycin resistance.