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Polymyxins Bind to the Cell Surface of Unculturable Acinetobacter baumannii and Cause Unique Dependent Resistance.
Advanced Science ( IF 14.3 ) Pub Date : 2020-06-08 , DOI: 10.1002/advs.202000704 Yan Zhu 1 , Jing Lu 1 , Mei-Ling Han 1 , Xukai Jiang 1 , Mohammad A K Azad 1 , Nitin A Patil 1 , Yu-Wei Lin 1 , Jinxin Zhao 1 , Yang Hu 1 , Heidi H Yu 1 , Ke Chen 1 , John D Boyce 1 , Rhys A Dunstan 1 , Trevor Lithgow 1 , Christopher K Barlow 2 , Weifeng Li 3 , Elena K Schneider-Futschik 4 , Jiping Wang 1 , Bin Gong 5 , Bjorn Sommer 6 , Darren J Creek 7 , Jing Fu 8 , Lushan Wang 9 , Falk Schreiber 6 , Tony Velkov 4 , Jian Li 1
Advanced Science ( IF 14.3 ) Pub Date : 2020-06-08 , DOI: 10.1002/advs.202000704 Yan Zhu 1 , Jing Lu 1 , Mei-Ling Han 1 , Xukai Jiang 1 , Mohammad A K Azad 1 , Nitin A Patil 1 , Yu-Wei Lin 1 , Jinxin Zhao 1 , Yang Hu 1 , Heidi H Yu 1 , Ke Chen 1 , John D Boyce 1 , Rhys A Dunstan 1 , Trevor Lithgow 1 , Christopher K Barlow 2 , Weifeng Li 3 , Elena K Schneider-Futschik 4 , Jiping Wang 1 , Bin Gong 5 , Bjorn Sommer 6 , Darren J Creek 7 , Jing Fu 8 , Lushan Wang 9 , Falk Schreiber 6 , Tony Velkov 4 , Jian Li 1
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Multidrug‐resistant Acinetobacter baumannii is a top‐priority pathogen globally and polymyxins are a last‐line therapy. Polymyxin dependence in A. baumannii (i.e., nonculturable on agar without polymyxins) is a unique and highly‐resistant phenotype with a significant potential to cause treatment failure in patients. The present study discovers that a polymyxin‐dependent A. baumannii strain possesses mutations in both lpxC (lipopolysaccharide biosynthesis) and katG (reactive oxygen species scavenging) genes. Correlative multiomics analyses show a significantly remodeled cell envelope and remarkably abundant phosphatidylglycerol in the outer membrane (OM). Molecular dynamics simulations and quantitative membrane lipidomics reveal that polymyxin‐dependent growth emerges only when the lipopolysaccharide‐deficient OM distinctively remodels with ≥ 35% phosphatidylglycerol, and with “patch” binding on the OM by the rigid polymyxin molecules containing strong intramolecular hydrogen bonding. Rather than damaging the OM, polymyxins bind to the phosphatidylglycerol‐rich OM and strengthen the membrane integrity, thereby protecting bacteria from external reactive oxygen species. Dependent growth is observed exclusively with polymyxin analogues, indicating a critical role of the specific amino acid sequence of polymyxins in forming unique structures for patch‐binding to bacterial OM. Polymyxin dependence is a novel antibiotic resistance mechanism and the current findings highlight the risk of ‘invisible’ polymyxin‐dependent isolates in the evolution of resistance.
中文翻译：
多粘菌素与不可培养的鲍曼不动杆菌的细胞表面结合并引起独特的依赖性耐药性。
多重耐药鲍曼不动杆菌是全球首要的病原体，多粘菌素是最后一线治疗。鲍曼不动杆菌中的多粘菌素依赖性（即在不含多粘菌素的琼脂上不可培养）是一种独特且高度耐药的表型，极有可能导致患者治疗失败。本研究发现多粘菌素依赖性鲍曼不动杆菌菌株的lpxC （脂多糖生物合成）和katG （活性氧清除）基因均存在突变。相关多组学分析显示细胞包膜显着重塑，外膜 (OM) 中磷脂酰甘油含量显着丰富。分子动力学模拟和定量膜脂质组学表明，只有当脂多糖缺陷的 OM 用 ≥ 35% 磷脂酰甘油进行独特重塑，并且含有强分子内氢键的刚性多粘菌素分子“补丁”结合在 OM 上时，才会出现多粘菌素依赖性生长。多粘菌素不会破坏 OM，而是与富含磷脂酰甘油的 OM 结合并增强膜的完整性，从而保护细菌免受外部活性氧的侵害。仅在多粘菌素类似物中观察到依赖性生长，表明多粘菌素的特定氨基酸序列在形成与细菌 OM 贴片结合的独特结构中发挥着关键作用。多粘菌素依赖性是一种新型抗生素耐药机制，目前的研究结果强调了耐药性进化过程中“看不见的”多粘菌素依赖性分离株的风险。
更新日期：2020-08-05
中文翻译：
多粘菌素与不可培养的鲍曼不动杆菌的细胞表面结合并引起独特的依赖性耐药性。
多重耐药鲍曼不动杆菌是全球首要的病原体，多粘菌素是最后一线治疗。鲍曼不动杆菌中的多粘菌素依赖性（即在不含多粘菌素的琼脂上不可培养）是一种独特且高度耐药的表型，极有可能导致患者治疗失败。本研究发现多粘菌素依赖性鲍曼不动杆菌菌株的lpxC （脂多糖生物合成）和katG （活性氧清除）基因均存在突变。相关多组学分析显示细胞包膜显着重塑，外膜 (OM) 中磷脂酰甘油含量显着丰富。分子动力学模拟和定量膜脂质组学表明，只有当脂多糖缺陷的 OM 用 ≥ 35% 磷脂酰甘油进行独特重塑，并且含有强分子内氢键的刚性多粘菌素分子“补丁”结合在 OM 上时，才会出现多粘菌素依赖性生长。多粘菌素不会破坏 OM，而是与富含磷脂酰甘油的 OM 结合并增强膜的完整性，从而保护细菌免受外部活性氧的侵害。仅在多粘菌素类似物中观察到依赖性生长，表明多粘菌素的特定氨基酸序列在形成与细菌 OM 贴片结合的独特结构中发挥着关键作用。多粘菌素依赖性是一种新型抗生素耐药机制，目前的研究结果强调了耐药性进化过程中“看不见的”多粘菌素依赖性分离株的风险。
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