Identification and development of antimicrobial peptoids effective against cross-kingdom biofilms

有效对抗跨界生物膜的抗菌肽的鉴定和开发

• 批准号: 9976086
• 负责人: Kevin Bicker
• 金额: $ 6.54万
• 依托单位: MIDDLE TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-18 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976086
• 关键词: Address; Agar; Antifungal Agents; Bacteria; Bacterial Infections; Biological Assay; Biological Availability; Candida albicans; Cell Survival; Cell membrane; Chemicals; Clinical; Complex; Cryptococcus neoformans; Development; Diffusion; Drug Design; Drug resistance; Drug usage; Funding; Goals; Hospitals; Immobilization; Immune system; Individual; Infection; Invaded; Lead; Length; Libraries; Measures; Methods; Microbe; Microbial Biofilms; Morbidity - disease rate; Mycoses; Nature; Nosocomial Infections; Organism; Pathogenicity; Peptide Hydrolases; Peptides; Peptoids; Prevalence; Prosthesis; Race; Reporter; Reporting; Research; Resistance; Source; Surface; Techniques; Testing; Therapeutic; Toxic effect; United States National Institutes of Health; Work; antimicrobial; antimicrobial drug; antimicrobial peptide; arm; combat; combinatorial; cytotoxicity; design; high throughput screening; improved; in vivo; ineffective therapies; mortality; pathogen; pathogenic bacteria; pathogenic fungus; peptidomimetics; polymicrobial biofilm; quorum sensing; screening; wound

Identification and development of antimicrobial peptoids effective against cross-kingdom biofilms Project Summary The purposed work focuses on identifying antimicrobial compounds targeting cross-kingdom biofilms generated by Candida albicans and bacteria through high-throughput screening of a one bead one compound combinatorial library. C. albicans is the third most common source of hospital acquired infections and the primary source of hospital acquired fungal infections, with high rates of morbidity and mortality. C. albicans often forms cross-kingdom polymicrobial biofilms with other infectious microbes. These cross-kingdom interactions can be synergistic and result in unique quorum-sensing that causes increased drug resistance. Antimicrobial drugs that treat both the fungal and the bacterial infections within a complex, synergistic biofilm would provide a valuable therapeutic option to those dealing with deadly hospital acquired cross-kingdom biofilm infections. Once such option could be antimicrobial peptoids. Peptoids are a useful class of peptidomimetics due to ease of synthesis, increased bioavailability, and decreased protease recognition compared with peptides. Our lab and others have demonstrated the antimicrobial efficacy of peptoids against both bacterial and fungal pathogens. Additionally, reports demonstrate modest efficacy of antimicrobial peptoids against both monospecial and cross-kingdom biofilms. However, the low throughput nature of these antimicrobial peptoid reports limits the compound chemical diversity and biofilm species variety they can explore. The overall goal of this proposal is to identify antimicrobial peptoids effective against C. albicans/bacterial cross-kingdom biofilms through the adaption and use of our previously developed PLAD high-throughput assay. Specific work proposed here will include the synthesis of several combinatorial peptoid libraries and screening of these libraries using our high-throughput Peptoid Library Agar Diffusion (PLAD) assay with subsequent testing to evaluate antibiofilm activity. Additionally, we will also adapt our PLAD assay to screen peptoid libraries against mature, established biofilms to directly generate peptoids with antibiofilm activity. Antibiofilm compounds rapidly identified using these techniques will be resynthesized and their broad antibiofilm activity and preliminary cytotoxicity evaluated using traditional methods to generate lead compounds. Successful completion of this work will result in antibiofilm peptoids that can be further developed into therapeutic options for individuals dealing with deadly cross-kingdom biofilm infections on wounds, prosthetics, and other surfaces.

抗跨界生物膜类抗菌肽的鉴定与开发 项目摘要 目的工作的重点是确定针对跨王国的抗菌化合物 通过高通量筛选单珠生物膜，由白色念珠菌和细菌产生生物膜 复合组合文库C.白色念珠菌是医院获得性感染的第三大常见来源。 感染和医院获得性真菌感染的主要来源，发病率高， mortality. C.白色念珠菌通常与其它感染性微生物形成跨界多微生物生物膜。 这些跨王国的相互作用可以是协同的，并导致独特的群体感应， 增加耐药性。治疗体内真菌和细菌感染的抗菌药物 一个复杂的，协同生物膜将提供一个有价值的治疗选择那些处理致命的 医院获得性跨王国生物膜感染。一旦这样的选择可能是抗微生物类肽。 类肽是一类有用的肽模拟物，因为其易于合成，生物利用度增加， 与肽相比，降低了蛋白酶识别。我们的实验室和其他人已经证明了 本发明提供了类肽对细菌和真菌病原体的抗微生物功效。此外，报告 证明抗微生物类肽对单特异性和跨界的适度功效 生物膜然而，这些抗微生物类肽报告的低通量性质限制了化合物的应用。 化学多样性和生物膜物种多样性，他们可以探索。本提案的总体目标是 鉴定对C.白念珠菌/细菌跨界生物膜 调整和使用我们以前开发的PLAD高通量测定。 这里提出的具体工作将包括几个组合类肽库的合成 并使用我们的高通量类肽文库琼脂扩散（PLAD）测定筛选这些文库 随后进行测试以评价涂膜活性。此外，我们还将调整我们的PLAD测定 针对成熟的、建立的生物膜筛选类肽文库，以直接产生具有 电影活动。使用这些技术快速鉴定的抗生物膜化合物将被重新合成 并使用传统方法评价了它们的广泛的生物膜活性和初步的细胞毒性， 产生铅化合物。这项工作的成功完成将产生可用于制备生物膜的类肽， 将进一步发展为治疗方案，用于处理致命的跨王国生物膜的个体 伤口、假体和其他表面的感染。