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.

项目总结/摘要 耳念珠菌是近年来出现的一种致病真菌，其感染可导致侵袭性疾病的高死亡率， 全球范围内的医院感染。这种真菌可以长期存在，因此经常会引起爆发。在 addition，C.耳对所有种类的抗真菌药物表现出高水平的抗性。即使是那些 最初对治疗选择的棘突菌素敏感，很快就会产生抗药性。因此， 迫切需要开发新的抗真菌药物来治疗这种病原体。抗微生物肽（AMP）是天然的 最近已经检查了它们作为治疗剂的效用， 抗生素和抗真菌药。它们的主要优点是微生物通常不会对细菌产生耐药性。 他们不幸的是，它们的生产成本很高，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类化合物的有效抗真菌活性， AMP的结构和活性。这些AMP模拟物对C.白色念珠菌 抗真菌和生物膜形成，以及抗耐药非白色念珠菌临床分离株。活动 是快速的，并且对芽生孢子和菌丝形式都是杀真菌的，并且念珠菌的抗性菌株已经失败 这表明它们是治疗C.耳感染。最近 这些模拟物在两种小鼠口腔念珠菌病模型中显示出有效的体内活性 并且在侵袭性念珠菌病模型中具有低的体内全身毒性。事实上，初步数据显示， 新设计的模拟物对C.耳体外培养。这些初步结果支持了以下假设： 这些化合物是活性的、无毒的，并且可以被开发成新的治疗性抗真菌剂， 治疗C.耳感染。为了获得足够的数据来深入调查这一点，这项探索性研究 提出检测AMP模拟物对C.耳。为了解决这个问题，提出了两个目标：1） 定量选择的AMP模拟物对C.耳临床分离株，并评价 体外抗性的发展; 2）定量选择的AMP模拟物的动力学和活性， 小鼠模型C.耳感染。这些目标的成功实现将为今后的工作奠定基础。 这些模拟化合物作为治疗C.耳，和其他潜在的新兴真菌 病原体