Antimicrobial peptide mimetic activity against Candida auris

针对耳念珠菌的抗菌肽模拟活性

• 批准号: 10369013
• 负责人: GILL DIAMOND
• 金额: $ 23.04万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-11 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10369013
• 关键词: Address; Antibiotics; Antifungal Agents; Candida; Candida albicans; Candida auris; Candidiasis; Cations; Characteristics; Chemistry; Clinical; Communicable Diseases; Dangerousness; Data; Development; Digestion; Disease Outbreaks; Drug Kinetics; Drug resistance; Environment; Exhibits; Future; Goals; Hour; Immunocompromised Host; In Vitro; Individual; Industrial fungicide; Infection; Kidney; Kinetics; Lead; Membrane; Microbe; Microbial Biofilms; Modeling; Multi-Drug Resistance; Nosocomial Infections; Oral candidiasis; Peptide Hydrolases; Pharmaceutical Preparations; Publishing; Research; Resistance; Resistance development; Series; Structure; Testing; Therapeutic; Toxic effect; Toxicology; antimicrobial drug; antimicrobial peptide; base; design; dosage; effective therapy; experimental study; fungus; immunosuppressed; in vivo; mimetics; mortality; mouse model; multi-drug resistant pathogen; novel therapeutics; pathogen; pathogenic fungus; peptidomimetics; resistant strain; small molecule; synergism; systemic toxicity; treatment choice; treatment response

Project Summary / Abstract Candida auris is a recently emerged pathogenic fungus, whose infections lead to high mortality in invasive nosocomial infections world-wide. The fungus can persist long-term, and thus can often cause outbreaks. In addition, C. auris exhibits high levels of resistance to all classes of antifungal drugs. Even those strains which are initially susceptible to echinochandins, the treatment of choice, rapidly develop resistance. Thus, there is an urgent need to develop new antifungal drugs to treat this pathogen. Antimicrobial peptides (AMPs) are naturally occurring, broad-spectrum antimicrobial agents that have been examined recently for their utility as therapeutic antibiotics and antifungals. Chief among their strengths is that microbes do not generally develop resistance to them. Unfortunately, they are expensive to produce and are often sensitive to protease digestion. We have recently demonstrated the potent antifungal activity of a series of inexpensive nonpeptidic compounds that mimic AMPs in both structure and activity. These AMP mimetics exhibit strong activity against C. albicans in both planktonic and biofilm forms, as well as against drug-resistant non-albicans Candida clinical isolates. The activity is rapid, and fungicidal against both blastoconidia and hyphal forms, and resistant strains of Candida have failed to be generated, suggesting that they are attractive candidates as drugs to treat C. auris infections. Most recently it was demonstrated that these mimetics exhibit potent in vivo activity in two mouse models of oral candidiasis and in a model of invasive candidiasis, with low in vivo systemic toxicity. Indeed, preliminary data show potent activity of newly designed mimetics against C. auris in vitro. These initial results support the hypothesis that these compounds are active, and non-toxic, and can be developed into novel therapeutic antifungal agents to treat C. auris infections. In order to obtain sufficient data to investigate this in depth, this exploratory study proposes to examine the activity of AMP mimetics against C. auris. To address this, two aims are proposed: 1) Quantify the antifungal activity of select AMP mimetics against C. auris clinical isolates, and evaluate the development of resistance in vitro; 2) Quantify the kinetics and activity of select AMP mimetics in mouse models of C. auris infection. Successful completion of these aims will provide the basis for future studies of these mimetic compounds as a treatment for C. auris, and potentially other emerging fungal pathogens.

项目概要/摘要 耳念珠菌是一种新近出现的致病真菌，其感染会导致侵入性感染的高死亡率。 全世界范围内的医院感染。这种真菌可以长期存在，因此经常会引起疫情爆发。在 此外，耳念珠菌对所有类别的抗真菌药物都表现出高水平的耐药性。即使是那些菌株 最初对棘白菌素敏感，选择治疗方法后，迅速产生耐药性。因此，有一个 迫切需要开发新的抗真菌药物来治疗这种病原体。抗菌肽 (AMP) 天然存在 最近出现的广谱抗菌剂，其治疗效用最近经过检验 抗生素和抗真菌药物。它们的主要优点是微生物通常不会产生抗药性 他们。不幸的是，它们的生产成本昂贵，并且通常对蛋白酶消化敏感。我们有 最近证明了一系列廉价的非肽化合物具有有效的抗真菌活性，这些化合物模仿 AMP 的结构和活性。这些 AMP 模拟物在两种情况下均表现出针对白色念珠菌的强大活性 浮游和生物膜形式，以及针对耐药非白色念珠菌临床分离株。活动内容 快速，并且对囊生孢子和菌丝形式都有杀菌作用，并且念珠菌的抗性菌株已失败 的产生，表明它们是治疗耳念珠菌感染的有吸引力的候选药物。最近 结果表明，这些模拟物在两种口腔念珠菌病小鼠模型中表现出有效的体内活性 在侵袭性念珠菌病模型中，具有较低的体内全身毒性。事实上，初步数据显示， 新设计的模拟物对耳念珠菌的体外活性。这些初步结果支持以下假设： 这些化合物具有活性、无毒，可开发成新型治疗性抗真菌药物 治疗耳念珠菌感染。为了获得足够的数据来深入研究这一问题，本次探索性研究 建议检查 AMP 模拟物针对耳念珠菌的活性。为了解决这个问题，提出了两个目标：1） 量化选定的 AMP 模拟物对耳念珠菌临床分离株的抗真菌活性，并评估 体外耐药性的发展； 2) 量化所选 AMP 模拟物的动力学和活性 耳念珠菌感染的小鼠模型。这些目标的成功实现将为今后的发展奠定基础 研究这些模拟化合物用于治疗耳念珠菌和其他潜在的新兴真菌 病原体。