Polymyxin-Induced Lipid A Deacylation in Pseudomonas aeruginosa Perturbs Polymyxin Penetration and Confers High-Level Resistance,ACS Chemical Biology

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Polymyxin-Induced Lipid A Deacylation in Pseudomonas aeruginosa Perturbs Polymyxin Penetration and Confers High-Level Resistance
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2017-12-11 00:00:00 , DOI: 10.1021/acschembio.7b00836
Mei-Ling Han _{1,

2} , Tony Velkov _{1,

3} , Yan Zhu ₂ , Kade D. Roberts ₁ , Anton P. Le Brun ₄ , Seong Hoong Chow ₂ , Alina D. Gutu ₅ , Samuel M. Moskowitz ₆ , Hsin-Hui Shen _{2,

7} , Jian Li ₂

Affiliation

Polymyxins are last-line antibiotics against life-threatening multidrug-resistant Gram-negative bacteria. Unfortunately, polymyxin resistance is increasingly reported, leaving a total lack of therapies. Using lipidomics and transcriptomics, we discovered that polymyxin B induced lipid A deacylation viapagL in both polymyxin-resistant and -susceptible Pseudomonas aeruginosa. Our results demonstrated that the deacylation of lipid A is an “innate immunity” response to polymyxins and a key compensatory mechanism to the aminoarabinose modification to confer high-level polymyxin resistance in P. aeruginosa. Furthermore, cutting-edge neutron reflectometry studies revealed that an assembled outer membrane (OM) with the less hydrophobic penta-acylated lipid A decreased polymyxin B penetration, compared to the hexa-acylated form. Polymyxin analogues with enhanced hydrophobicity displayed superior penetration into the tail regions of the penta-acylated lipid A OM. Our findings reveal a previously undiscovered mechanism of polymyxin resistance, wherein polymyxin-induced lipid A remodeling affects the OM packing and hydrophobicity, perturbs polymyxin penetration, and thereby confers high-level resistance.

中文翻译：

铜绿假单胞菌中多粘菌素诱导的脂质A脱酰作用扰动了多粘菌素的渗透并赋予了高水平的抗性

多粘菌素是针对威胁生命的多药耐药革兰氏阴性细菌的最后一道抗生素。不幸的是，对多粘菌素耐药性的报道越来越多，完全缺乏治疗方法。使用脂质组学和转录组学，我们发现多粘菌素B在多粘菌素耐药性和易感性铜绿假单胞菌中均通过pagL诱导了脂质A的脱酰作用。我们的结果表明，脂质A的脱酰作用是对多粘菌素的“先天免疫”反应，也是对铜绿假单胞菌赋予高水平多粘菌素抗性的氨基阿拉伯糖修饰的关键补偿机制。。此外，最先进的中子反射测量研究表明，与六酰化形式相比，具有较少疏水性的五酰化脂质A的组装外膜（OM）降低了多粘菌素B的渗透。具有增强的疏水性的多粘菌素类似物表现出优异的渗透性，进入五酰化脂质A OM的尾部区域。我们的发现揭示了以前未发现的多粘菌素抗性机制，其中多粘菌素诱导的脂质A重塑会影响OM堆积和疏水性，扰乱多粘菌素的渗透，从而赋予高水平的抗性。

更新日期：2017-12-11

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