The Remarkable Innate Resistance of Burkholderia bacteria to Cationic Antimicrobial Peptides: Insights into the Mechanism of AMP Resistance.
The Remarkable Innate Resistance of Burkholderia bacteria to Cationic Antimicrobial Peptides: Insights into the Mechanism of AMP Resistance.
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DOI：
10.1007/s00232-022-00232-2
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发表时间：
2022-10
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--
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中科院分区：
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属于伯克氏菌属的革兰氏阴性菌对广谱、阳离子、抗菌肽（AMPs）具有显著的耐药性。有人提出，这种先天抗性与外膜脂多糖（OM LPS）的变化有关，包括外膜脂质A磷酸基与阳离子4-氨基-4-脱氧阿拉伯糖的基本修饰。这种修饰减少了OM LPS上的整体负电荷，从而改变OM结构，减少阳离子amp的结合、积累和渗透。同样，革兰氏阴性病原体铜绿假单胞菌可以通过多种机制迅速对许多AMPs产生抗性，通常包括激活arn操纵子，这导致短暂地对脂质a进行相同的修饰。我们最近发现了一组合成进化的AMPs，它们在铜绿假单胞菌中多次传代不会引起任何抗性，因此显然不受P. aeruginosa中脂质a的氨基糖基化抑制。在这里，我们测试了这些抗性避免肽，在一组18个有效的amp，对泰国伯克霍尔德氏菌。我们发现所有的AMPs对泰国芽孢杆菌都没有可测量的活性。有些在高达150 μM的浓度下无活性，尽管它们在≤10 μM的浓度下对一组常见的人类细菌病原体（包括铜绿假单胞菌）具有杀菌活性。我们推测，伯克霍尔德菌属成员的脂质A的组成性修饰只是更广泛的修饰的一部分，这些修饰改变了OM的结构，从而提供了对阳离子amp的显著抗性。
Gram-negative bacteria belonging to the genus Burkholderia are remarkably resistant to broad spectrum, cationic, antimicrobial peptides (AMPs). It has been proposed that this innate resistance is related to changes in the outer membrane lipopolysaccharide (OM LPS), including the constitutive, essential modification of outer membrane Lipid A phosphate groups with cationic 4-amino-4-deoxy-arabinose. This modification reduces the overall negative charge on the OM LPS which may change the OM structure and reduce the binding, accumulation, and permeation of cationic AMPs. Similarly, the Gram-negative pathogen Pseudomonas aeruginosa can quickly become resistant to many AMPs by multiple mechanisms, frequently including activation of the arn operon, which leads, transiently, to the same modification of Lipid A. We recently discovered a set of synthetically evolved AMPs that do not invoke any resistance in P. aeruginosa over multiple passages, and thus are apparently not inhibited by aminorabinosylation of Lipid A in P. aeruginosa. Here we test these resistance avoiding peptides, within a set of 18 potent AMPs, against Burkholderia thailandensis. We find that none of the AMPs tested have measurable activity against B thailandensis. Some were inactive at concentrations as high as 150 μM, despite all having sterilizing activity at ≤ 10 μM against a panel of common, human bacterial pathogens, including P. aeruginosa. We speculate that the constitutive modification of Lipid A in members of the Burkholderia genus is only part of a broader set of modifications that change the architecture of the OM to provide such remarkable levels of resistance to cationic AMPs.
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影响因子：
6.4
作者：
Khanolkar RA;Clark ST;Wang PW;Hwang DM;Yau YCW;Waters VJ;Guttman DS
通讯作者：
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影响因子：
3.2
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影响因子：
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通讯作者：
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影响因子：
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