Cationic Amphiphiles Increase Activity of Aminoglycoside Antibiotic Tobramycin in the Presence of Airway Polyelectrolytes
Cationic Amphiphiles Increase Activity of Aminoglycoside Antibiotic Tobramycin in the Presence of Airway Polyelectrolytes
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DOI：
10.1021/ja803925n
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发表时间：
2009-01-21
影响因子：
15
通讯作者：
Wong, Gerard C. L.
中科院分区：
文献类型：
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作者：
Drew, Kirstin R. Purdy;Sanders, Lori K.;Wong, Gerard C. L.
经验表明，因细菌感染而存在于囊性纤维化（CF）气道中的阴离子聚电解质会通过静电结合显著降低阳离子抗菌剂的活性。在这项工作中，我们利用同步辐射小角X射线散射来研究妥布霉素（一种通常通过吸入方式给予CF患者的氨基糖苷类抗生素）与在CF气道中浓度较高的DNA之间的相互作用。我们发现，两亲分子混合物的存在会显著改变DNA和妥布霉素之间的相互作用。我们测量了妥布霉素、DNA以及两亲混合物之间形成的自组装结构的层次，并展示了如何控制这些组分之间的相互作用。结果表明，通过电荷匹配和曲率匹配优化的用于结合DNA的阳离子和负曲率两亲分子的混合物能够竞争性地将与DNA结合的妥布霉素置换出来，从而极大地抑制妥布霉素 - DNA结合以及由此导致的抗菌失活。生长抑制试验证实，在添加两亲分子的情况下，妥布霉素在有DNA存在时活性增强。这些结果表明，优化的阳离子两亲分子溶液有可能在含有高浓度阴离子炎症聚合物的高度感染环境中增强抗菌功能。
It is empirically known that anionic polyelectrolytes present in cystic fibrosis (CF) airways due to bacterial infection significantly decrease the activity of cationic antimicrobials via electrostatic binding. In this work, we use synchrotron small-angle X-ray scattering to investigate the interaction between tobramycin, an aminoglycoside antibiotic commonly administered to CF patients via inhalation, with DNA, which is found in high concentrations in the CIF airway. We find that interactions between DNA and tobramycin are significantly modified by the presence of mixtures of amphiphilic molecules. We measure a hierarchy of self-assembled structures formed between tobramycin, DNA, and the amphiphile mixtures and show how interactions between these components can be controlled. Results indicate that mixtures of cationic and negative curvature amphiphiles optimized for DNA binding via charge matching and curvature matching can competitively displace bound tobramycin from DNA and thereby drastically suppress tobramycin-DNA binding and resultant antimicrobial inactivation. Growth inhibition assays confirm the increased activity of tobramycin in the presence of DNA with the addition of the amphiphiles. These results suggest that optimized cationic amphiphile solutions have the potential to enhance antimicrobial function in highly infected environments that contain increased concentrations of anionic inflammatory polymers.