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.
Thesaurus Terms: antibiotic, cornea, drug discovery /isolation, eye infection, pore forming protein cell differentiation, cell proliferation, complementary DNA, corneal epithelium, peptide chemical synthesis genetic screening, molecular cloning, polymerase chain reaction, tissue /cell culture
