Staphylococcal phenotypes induced by naturally occurring and synthetic membrane-interactive polyphenolic β-lactam resistance modifiers.
Staphylococcal phenotypes induced by naturally occurring and synthetic membrane-interactive polyphenolic β-lactam resistance modifiers.
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DOI：
10.1371/journal.pone.0093830
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Taylor PW
中科院分区：
文献类型：
--
作者：
Palacios L;Rosado H;Micol V;Rosato AE;Bernal P;Arroyo R;Grounds H;Anderson JC;Stabler RA;Taylor PW
没食子儿茶素，特别是(-)-表儿茶素没食子酸酯（ECg），具有消除耐甲氧西林金黄色葡萄球菌（MRSA）菌株β-内酰胺耐药性的能力；它们还可以阻止生物膜的形成，减少大部分外蛋白质组的分泌，并诱导细胞形态的深刻变化。目前的证据表明，这些可逆的表型性状是由于它们嵌入细菌的细胞质膜。我们已经努力通过逐步去除天然分子的b环药效团和A:C融合环系统中的羟基来增强ECg修饰MRSA表型的能力。ECg与细胞膜迅速结合，诱导负责保护细胞壁应激和维持细胞膜完整性和功能的基因上调。以葡萄球菌双分子层脂质组成为模型的人工膜研究表明，ECg位于脂质栅栏深处，引起双分子层热致性行为的重大改变。非没食子酸同系物表儿茶素通过促进ECg分子进入细胞膜而增强了ECg介导的作用。与ECg相比，具有非自然b环羟基化模式的ECg类似物诱导了更高水平的基因表达和更深刻的MRSA膜流动性变化，但在双层中采用了更浅层的位置。ECg对带正电的葡萄球菌膜具有高度亲和力，并诱导双分子层的生物物理特性发生变化，这可能解释了其分散细胞壁生物合成机制的能力，导致β-内酰胺抗性。通过ECg的化学修饰来增强这些特性的能力提高了开发更有效的类似物用于临床评估的可能性。
Galloyl catechins, in particular (-)-epicatechin gallate (ECg), have the capacity to abrogate β-lactam resistance in methicillin-resistant strains of Staphylococcus aureus (MRSA); they also prevent biofilm formation, reduce the secretion of a large proportion of the exoproteome and induce profound changes to cell morphology. Current evidence suggests that these reversible phenotypic traits result from their intercalation into the bacterial cytoplasmic membrane. We have endeavoured to potentiate the capacity of ECg to modify the MRSA phenotype by stepwise removal of hydroxyl groups from the B-ring pharmacophore and the A:C fused ring system of the naturally occurring molecule. ECg binds rapidly to the membrane, inducing up-regulation of genes responsible for protection against cell wall stress and maintenance of membrane integrity and function. Studies with artificial membranes modelled on the lipid composition of the staphylococcal bilayer indicated that ECg adopts a position deep within the lipid palisade, eliciting major alterations in the thermotropic behaviour of the bilayer. The non-galloylated homolog (-)-epicatechin enhanced ECg-mediated effects by facilitating entry of ECg molecules into the membrane. ECg analogs with unnatural B-ring hydroxylation patterns induced higher levels of gene expression and more profound changes to MRSA membrane fluidity than ECg but adopted a more superficial location within the bilayer. ECg possessed a high affinity for the positively charged staphylococcal membrane and induced changes to the biophysical properties of the bilayer that are likely to account for its capacity to disperse the cell wall biosynthetic machinery responsible for β-lactam resistance. The ability to enhance these properties by chemical modification of ECg raises the possibility that more potent analogs could be developed for clinical evaluation.
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影响因子：
7.4
作者：
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通讯作者：
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影响因子：
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影响因子：
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通讯作者：
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