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

抗跨界生物被膜抗菌肽的鉴定及研究进展 项目摘要 有目的的工作集中在鉴定针对跨领域的抗微生物化合物。 单珠菌高通量筛选白色念珠菌和细菌生物被膜 复合组合库。白念珠菌是医院获得性肺炎的第三大来源 感染和医院获得性真菌感染的主要来源，发病率和 死亡率。白色念珠菌经常与其他感染性微生物形成跨王国的多菌生物膜。 这些跨领域的互动可以是协同的，并导致独特的群体感应，从而导致 抗药性增强。既治疗真菌感染又治疗细菌感染的抗微生物药物 一种复杂的、协同的生物膜将为那些处理致命疾病的人提供一个有价值的治疗选择 医院获得性跨境生物被膜感染。一旦这样的选择可能是抗菌肽类药物。 类肽是一类有用的类肽类药物，因为它易于合成，生物利用度提高，以及 与多肽相比，酶的识别率降低。我们的实验室和其他实验室已经证明了 类肽对细菌和真菌病原体的抗菌效果。此外，报告 显示抗菌肽对单一物种和跨领域的适度疗效 生物膜。然而，这些抗菌肽报告的低通量性质限制了该化合物的使用。 他们可以探索化学多样性和生物膜物种多样性。这项提案的总体目标是 通过鉴定对白色念珠菌/细菌跨界生物被膜有效的抗菌肽 我们以前开发的PLAD高通量检测方法的适应和使用。 这里提出的具体工作将包括合成几个组合类肽文库 并使用我们的高通量Peptoid文库琼脂扩散(PLAD)试验筛选这些文库 并进行后续测试以评估抗生物膜的活性。此外，我们还将调整我们的PLAD检测 针对成熟的已建立的生物膜筛选类肽文库，以直接产生类肽 抗生物膜活性。利用这些技术快速鉴定的抗生物膜化合物将被重新合成 和它们广泛的抗菌膜活性和初步的细胞毒性评价使用传统的方法 生成先导化合物。这项工作的成功完成将导致抗菌膜类肽可以 进一步发展成为处理致命跨王国生物膜的个人的治疗选择 伤口、假肢和其他表面的感染。

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.