抗菌肽在眼科的应用：角膜保存及细菌性角膜炎治疗的实验研究
The use of antimicrobial peptides in ophthalmology: an experimental study in corneal preservation and the management of bacterial keratitis.
作者信息
Mannis Mark J
机构信息
Cornea Research Laboratory, Department of Ophthalmology, University of California, Davis, USA.
出版信息
Trans Am Ophthalmol Soc. 2002;100:243-71.
PURPOSE
Bacterial keratitis is an ocular infection with the potential to cause significant visual impairment. Increasing patterns of antibiotic resistance have necessitated the development of new antimicrobial agents for use in bacterial keratitis and other serious ocular infections. With a view to exploring the use of novel antimicrobial peptides in the management of ocular infection, we performed a series of experiments using synthetic antimicrobial peptides designed for the eradication of common and serious ophthalmic pathogens.
METHODS
Experiments were performed with three clinical ocular isolates--Pseudomonas aeruginosa, Staphylococcus aureus, and Staphylococcus epidermidis--in three experimental settings: (1) in vitro in a controlled system of 10 mM sodium phosphate buffer, (2) in vitro in modified chondroitin sulfate-based corneal preservation media (Optisol), and (3) in an in vivo animal model (rabbit) simulating bacterial keratitis. In all cases, outcomes were measured by quantitative microbiological techniques.
RESULTS
The candidate peptides (CCI A, B, and C and COL-1) produced a total reduction of the test pathogens in phosphate buffered saline. In modified Optisol, the peptides were effective against S epidermidis at all temperatures, demonstrated augmented activity at 23 degrees C against the gram-positive organisms, but were ineffective against P aeruginosa. The addition of EDTA to the medium augmented the killing of P aeruginosa but made no difference in the reduction of gram-positive organisms. In an in vivo rabbit model of Pseudomonas keratitis, COL-1 demonstrated neither clinical nor microbicidal efficacy and appeared to have a very narrow dosage range, outside of which it appeared to be toxic to the ocular surface.
CONCLUSION
Our data indicate that the antimicrobial peptides we tested were effective in vitro but not in vivo. In an age of increasing antibiotic resistance, antimicrobial peptides, developed over millions of years as innate defense mechanisms by plants and animals, may have significant potential for development as topical agents for the management of severe bacterial keratitis. However, modifications of the peptides, the drug delivery systems, or both, will be necessary for effective clinical application.
目的
细菌性角膜炎是一种可导致严重视力损害的眼部感染。抗生素耐药性模式的增加使得开发用于细菌性角膜炎和其他严重眼部感染的新型抗菌药物成为必要。为了探索新型抗菌肽在眼部感染治疗中的应用，我们使用设计用于根除常见和严重眼科病原体的合成抗菌肽进行了一系列实验。
方法
使用三种临床眼部分离株——铜绿假单胞菌、金黄色葡萄球菌和表皮葡萄球菌——在三种实验环境中进行实验：（1）在体外10 mM磷酸钠缓冲液的受控系统中，（2）在体外基于硫酸软骨素的改良角膜保存介质（Optisol）中，以及（3）在模拟细菌性角膜炎的体内动物模型（兔）中。在所有情况下，通过定量微生物技术测量结果。
结果
候选肽（CCI A、B和C以及COL-1）在磷酸盐缓冲盐水中使测试病原体总数减少。在改良的Optisol中，这些肽在所有温度下对表皮葡萄球菌均有效，在23摄氏度时对革兰氏阳性菌表现出增强的活性，但对铜绿假单胞菌无效。向培养基中添加乙二胺四乙酸（EDTA）增强了对铜绿假单胞菌的杀灭作用，但对革兰氏阳性菌数量的减少没有影响。在铜绿假单胞菌角膜炎的体内兔模型中，COL-1既未显示出临床疗效也未显示出杀菌效果，并且似乎具有非常窄的剂量范围，超出该范围它似乎对眼表有毒性。
结论
我们的数据表明，我们测试的抗菌肽在体外有效，但在体内无效。在抗生素耐药性不断增加的时代，作为植物和动物数百万年进化而来的固有防御机制的抗菌肽，可能具有作为治疗严重细菌性角膜炎的局部药物的巨大开发潜力。然而，为了有效临床应用，肽、药物递送系统或两者都需要进行改进。
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