Novel Antimicrobials: Salivary MUC7 Peptides

产品说明：随着病原体对常规抗微生物剂的耐药性的出现以及一些抗真菌剂的毒性，迫切需要开发具有新作用机制的新药剂。一个有前途的来源是阳离子抗菌肽。我们已经发现人唾液粘蛋白MUC 7肽（来源于N-末端）在体外具有显著和广谱的抗微生物活性。这些阳离子肽对多种真菌（例如，C.白色念珠菌和C.新型细菌，导致免疫功能低下患者，特别是HIV/AIDS患者中常见机会性感染的生物体），以及革兰氏阳性和阴性细菌（例如，S.与龋齿有关的变形链球菌和与牙周病有关的牙龈卟啉单胞菌）。MUC 7 20-mer和12-mer在口腔中发现的生理样条件下保留相当大的杀念珠菌活性。12-mer与组胺素-5-12-mer或阿替霉素-B组合以协同或相加的方式对抗C。白色念珠菌和C.新人类最新添加的12-mer-D异构体在高离子强度缓冲液和唾液中表现出更强的杀念珠菌活性，并且比12-mer-L（天然形式）溶血性更低。这些发现支持并加强了我们的假设，即这些新的肽确实是治疗性和预防性抗微生物剂的合适候选物。此外，它们对哺乳动物细胞几乎没有毒性或没有毒性，并且引起耐药性的倾向很低。 本申请中提出的工作将进一步评估MUC 7肽作为体外和体内治疗剂的潜力，并继续检查其作用机制。在具体目标1中，将详细检查MUC 7 12-mer肽的抗微生物活性，包括与其他抗微生物剂的组合。在具体目标2中，我们将阐述MUC 7肽的作用机制，包括细胞内靶点、与核酸的潜在结合、蛋白质和核酸合成的抑制以及MUC 7肽对C. albicans和S.酿酒酵母的基因表达谱。具体目标3将解决这些肽的生物可降解聚合物和/或水凝胶聚合物递送系统的配制和体外测试。在具体目标4中，我们将在体内模型中测试专门设计的递送系统对真菌感染的功效。总之，这些努力试图将MUC 7肽推向临床应用的长期目标。

DESCRIPTION: With the emergence of pathogens resistant to conventional antimicrobials, and toxicity of some antimycotics, there is an urgent need for development of new agents with novel mechanisms of action. One promising source is cationic antimicrobial peptides. We have discovered that human salivary mucin MUC7 peptides (derived from the N-terminus) possess significant and broad-spectrum antimicrobial activity m vitro. These cationic peptides are effective against a variety of fungi (e.g., C. albicans and C. neoformans, organisms responsible for the common opportunistic infections in immunocompromised patients, particularly those with HIV/AIDS), and both Gram-positive and negative bacteria (e.g. S. mutans, implicated in dental caries and P. gingivalis, implicated in periodontal diseases). MUC7 20-mer and 12-mer retain considerable candidacidal activity in physiological-like conditions found in the oral cavity. The 12-mer in combination with histatin-5-12-mer or amphotericin-B acts in a synergistic or additive manner against C. albicans and C. neoformans. A newest addition, 12-mer-D isomer exhibits more potent candidacidal activity in high-ionic strength buffers and in saliva, and is less hemolytic than the 12-mer-L (natural form). These finding support and strengthen our hypothesis that these novel peptides are indeed suitable candidates for therapeutic and preventive antimicrobials. Further, that they will show little or no toxicity toward mammalian cells and will have low tendency to elicit resistance. The work proposed in this application will further evaluate the MUC7 peptide potential as therapeutic agents in vitro and m vivo, and continue to examine their mechanism of action. In Specific Aim 1, MUC7 12-mer peptide antimicrobial activity will be examined in detail, including in combination with other antimicrobial agents. In Specific Aim 2, we will address the mechanism of MUC7 peptide action, including intracellular target(s), potential binding to nucleic acid, inhibition of protein and nucleic acid synthesis, and the effect of MUC7 peptide on C. albicans and S. cerevisiae by gene expression profiling. Specific Aim 3 will address the formulation and in vitro testing of biodegradable polymeric and/or hydrogel polymeric delivery systems for these peptides. In Specific Aim 4, we will test the efficacy of the specifically design delivery systems against fungal infections in vivo models. Altogether, these efforts attempt to move the MUC7 peptides toward the long-range goal of clinical application.