Mammal Cecropins as Antibiotics for Corneal Infections

描述（由申请人提供）：对当前抗生素库具有耐药性的新出现的细菌感染加速了对具有新作用机制的治疗剂的研究。近年来的研究表明，基因编码肽抗生素作为新一代的治疗药物具有很大的前景。这些药物有可能成为眼科医生日常使用的药物，用于治疗或预防眼部感染，特别是那些由对其他药物有耐药性的细菌引起的感染。Cecropins是一种结构相关的小肽家族，最初从无脊椎动物中分离出来，对广泛的革兰氏阴性和革兰氏阳性细菌有效。天蚕素形成两亲螺旋，锚定并穿透细菌细胞膜表面，导致细胞裂解。尽管哺乳动物已经进化出适应性免疫反应，但它们也保留了许多古老的基因，编码具有杀菌活性的产物，作为先天免疫反应发挥作用。鉴于猪天蚕素（cecropin P1）已经被鉴定和表征，并且天蚕素对杀死包括角膜感染中常见的微生物具有高度特异性，我们认为人类保留了天蚕素同源基因，其产物可以作为眼科临床使用的新抗生素。

DESCRIPTION (provided by applicant): The emerging bacterial infections that are resistant to the current antibiotic arsenal have accelerated search for therapeutic agents with a novel mechanism of action. Recent studies suggest that the gene-encoded peptide antibiotics may hold great promise as a new generation of therapeutic agents. These agents have the potential to become medications used on a daily basis by ophthalmologists to treat or prevent ocular infections, especially those infections caused by bacteria resistant to other drugs. Cecropins, a family of structurally related small peptides originally isolated from invertebrates, are potent against a wide spectrum of gram-negative and gram-positive bacteria. Cecropins form an amphipathic helix, which anchors to and penetrate the surface of bacterial cell membrane, resulting in cell lysis. Whereas mammals have evolved an adaptive immune response they also retain many ancient genes encoding products with bactericidal activities, functioning as an innate immune response. Given that a porcine cecropin (cecropin P1) has been identified and characterized and that cecropins are highly specific for killing microorganisms including those commonly found in corneal infections we propose that humans have retained cecropin-homologous genes whose products can be explored as new antibiotics used in the ophthalmic clinics. The major goals of this project are to identify and characterize the human homologue of cecropin P1 and to explore cecropin P1 and its human counterpart for commercial applications as novel antibiotics in ophthalmology. It is anticipated that the studies proposed in this Phase I application will result in structural and functional characterization of human cecropin. Phase II will be aimed at testing the efficacy and potential side-effects of mammalian cecropins using animal model systems as well as at regulatory submission and clinical testing.