Department of Chemical Engineering, Biomolecular Science and Engineering, University of California, Santa Barbara, California 93106, USA.
Pharm Res. 2010 Jul;27(7):1264-72. doi: 10.1007/s11095-010-0095-9. Epub 2010 Mar 20.
Developing microbicides for topical epithelial applications is extremely challenging, as evidenced by the scarcity of approved products even after decades of research. Chemical enhancers, including surfactants, are known to be effective antimicrobial agents but are typically toxic towards epithelial cells. Here, we report on the discovery of unique surfactant formulations with improved safety and efficacy profile for epithelial applications, via a combination of high throughput screening techniques.
Over three-hundred formulations derived from nine surfactants were screened for antibacterial properties against E. coli in vitro. A subset of these formulations showed high antibacterial activity and was screened for cytotoxicity in vitro. Formulations showing high antibacterial activity and reduced cytotoxicity compared to their individual components were tested for efficacy against B. thailendensis, a model for melioidosis-causing B. pseudomallei.
Lead formulations showed lower toxicity towards epidermal keratinocytes, with LC(50) values up to 3.5-fold higher than their component surfactants, while maintaining antibacterial efficacy against B. thailendensis.
Our results demonstrate that such a combinatorial screening approach can be used for designing safe and potent microbicides for epithelial applications.
开发用于局部上皮应用的杀微生物剂极具挑战性，即使经过数十年的研究，获得批准的产品仍然很少，这证明了这一点。化学增溶剂，包括表面活性剂，已被证实为有效的抗菌剂，但通常对上皮细胞具有毒性。在这里，我们通过高通量筛选技术的组合，报告了具有改善的安全性和上皮应用功效特征的独特表面活性剂配方的发现。
对来自 9 种表面活性剂的 300 多种配方进行了筛选，以检测其对大肠杆菌的体外抗菌性能。这些配方中的一部分显示出高抗菌活性，并在体外进行了细胞毒性筛选。与它们的单个成分相比，显示出高抗菌活性和降低的细胞毒性的配方被测试用于治疗类鼻疽伯克霍尔德氏菌，这是导致类鼻疽的假鼻疽伯克霍尔德氏菌的模型。
主要配方对表皮角质形成细胞的毒性较低，LC（50）值比其成分表面活性剂高 3.5 倍，同时保持对类鼻疽伯克霍尔德氏菌的抗菌功效。
我们的结果表明，这种组合筛选方法可用于设计用于上皮应用的安全有效的杀微生物剂。
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