Investigating the Interaction of Octapeptin A3 with Model Bacterial Membranes.
Investigating the Interaction of Octapeptin A3 with Model Bacterial Membranes.
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DOI：
10.1021/acsinfecdis.7b00065
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发表时间：
2017-08-11
影响因子：
5.3
通讯作者：
Velkov T
中科院分区：
文献类型：
--
作者：
Han ML;Shen HH;Hansford KA;Schneider EK;Sivanesan S;Roberts KD;Thompson PE;Le Brun AP;Zhu Y;Sani MA;Separovic F;Blaskovich MAT;Baker MA;Moskowitz SM;Cooper MA;Li J;Velkov T
八肽是环脂肽，其不表现出与多粘菌素的交叉抗性，并且具有包括真菌和革兰氏阳性细菌的更广谱的活性。在本研究中，我们研究了八肽素A3与革兰氏阴性病原体铜绿假单胞菌的不对称外膜模型的相互作用，使用中子反射法，连同荧光和量热法。我们的中子反射仪结果首次揭示了八肽素A3与革兰氏阴性外膜的相互作用涉及与磷脂和脂质A头基的初始瞬时极性相互作用，然后整个八肽素分子渗透到脂肪中。外膜的酰基核心。该机制与特异性靶向脂质A的多粘菌素B的机制形成对比，而八肽蛋白似乎靶向脂质A和磷脂两者。此外，八肽的机制似乎并不高度依赖于与脂质A的初始互补静电相互作用，这解释了它们与多粘菌素抗性革兰氏阴性细菌的脂质A结合的能力，所述脂质A被阳离子部分修饰，所述阳离子部分用于静电排斥阳离子多粘菌素分子。所提出的研究结果揭示了octapeptin穿透多粘菌素耐药革兰氏阴性病原体外膜的机制，并强调了它们作为针对有问题的多重耐药病原体的新抗生素开发的候选者的潜力。
Octapeptins are cyclic lipopeptides that do not exhibit cross-resistance with polymyxins and have a broader spectrum of activity that includes fungi and Gram-positive bacteria. In the present study we investigated the interaction of octapeptin A3 with asymmetric outer membrane models of the Gram-negative pathogen Pseudomonas aeruginosa, using neutron reflectometry, together with fluorimetric and calorimetry methods. For the first time our neutron reflectometry results reveal that the interaction of octapeptin A3 with the Gram-negative outer membrane involves an initial transient polar interaction with the phospholipid and lipid A head groups, followed by the penetration of the entire octapeptin molecule into the fatty acyl core of the outer membrane. This mechanism contrasts that of polymyxin B which specifically targets lipid A, whereas octapeptins appear to target both lipid A and phospholipids. Furthermore, the mechanism of octapeptins does not appear to be highly dependent on an initial complimentary electrostatic interaction with lipid A, which accounts for their ability to bind to the lipid A of polymyxin-resistant Gram-negative bacteria which is modified with cationic moieties that act to electrostatically repel the cationic polymyxin molecule. The presented findings shed new light on the mechanism whereby octapeptins penetrate the outer membrane of polymyxin-resistant Gram-negative pathogens and highlight their potential as candidates for development as new antibiotics against problematic multi-drug resistant pathogens.
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影响因子：
3.3
作者：
PARKER, WL;RATHNUM, ML
通讯作者：
RATHNUM, ML
DOI：
10.1007/s00249-014-0970-0
发表时间：
2014-09-01
影响因子：
2
作者：
Sani, Marc-Antoine;Gagne, Eve;Separovic, Frances
通讯作者：
Separovic, Frances
影响因子：
3.2
作者：
Moskowitz, SM;Ernst, RK;Miller, SI
通讯作者：
Miller, SI
影响因子：
2.9
作者：
Lee, CH;Tsai, CM
通讯作者：
Tsai, CM
影响因子：
16.6
作者：
Shen HH;Leyton DL;Shiota T;Belousoff MJ;Noinaj N;Lu J;Holt SA;Tan K;Selkrig J;Webb CT;Buchanan SK;Martin LL;Lithgow T
通讯作者：
Lithgow T