Novel Antimicrobials: Salivary MUC7 Peptides

新型抗菌剂：唾液 MUC7 肽

• 批准号: 7115328
• 负责人: LIBUSE ANNA BOBEK
• 金额: $ 24.74万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-03-15 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7115328
• 关键词: Candida albicans; Saccharomyces cerevisiae; antibacterial agents; antifungal agents; antiinfective agents; biodegradable product; biofilm; candidiasis; clinical research; confocal scanning microscopy; drug delivery systems; drug design /synthesis /production; drug screening /evaluation; gene expression profiling; human subject; laboratory mouse; mass spectrometry; microarray technology; mucins; nonhuman therapy evaluation; nucleic acid biosynthesis; peptide chemical synthesis; pharmacokinetics; polymers; protein biosynthesis; saliva

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.

随着病原体对常规抗菌素的耐药性和一些抗真菌药物的毒性的出现，迫切需要开发具有新的作用机制的新药物。一个有希望的来源是阳离子抗菌肽。我们已经发现人类唾液黏液蛋白MUC7肽（来源于n端）具有显著的广谱体外抗菌活性。这些阳离子肽对多种真菌（例如，白色念珠菌和新生念珠菌，它们是免疫功能低下患者，特别是艾滋病毒/艾滋病患者中常见的机会性感染的病原体）以及革兰氏阳性和阴性细菌（例如，与龋齿有关的变形链球菌和与牙周病有关的牙龈假单胞菌）都有效。MUC7 20-mer和12-mer在口腔中发现的生理样条件下保持相当大的候选菌活性。12-mer与组蛋白-5-12-mer或两性霉素- b联合作用，对白色念珠菌和新生念珠菌具有协同或加性作用。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候选菌活性，并且比12-mer-L（天然形式）的溶血作用更小。这些发现支持并加强了我们的假设，即这些新型肽确实是治疗性和预防性抗菌剂的合适候选者。此外，它们对哺乳动物细胞的毒性很小或没有毒性，引起耐药性的倾向也很低。