Development of novel chemical series of Candida albicans biofilm inhibitors

白色念珠菌生物膜抑制剂新型化学系列的开发

• 批准号: 8951343
• 负责人: Jose L. Lopez-Ribot
• 金额: $ 36.75万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-22 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8951343
• 关键词: Action Potentials; Advanced Development; Animal Model; Anti-Bacterial Agents; Antibiotics; Antifungal Agents; Antifungal Therapy; Biological; Biological Assay; Biology; Candida albicans; Candidiasis; Catheters; Chemical Structure; Chemicals; Collection; Communicable Diseases; Development; Disseminated candidiasis; Feedback; Goals; Health Care Costs; Hospitals; Immune; In Vitro; Incidence; Infection; Lead; Link; Microbial Biofilms; Microbiology; Modeling; Molecular Target; Morbidity - disease rate; Mus; Mycoses; Nature; Oral candidiasis; Pathogenesis; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Population; Prevention; Process; Property; RNA Sequences; Research Personnel; Resistance; Resistance development; Safety; Serial Passage; Series; Structure-Activity Relationship; Surface; Testing; Time; Toxic effect; Vision; analog; candidemia; chemical property; clinically relevant; cost; design; drug development; fungus; high risk; improved; in vivo; inhibitor/antagonist; innovation; insight; lead series; microbial community; mortality; mutant; novel; novel strategies; preclinical study; public health relevance; research study; screening; small molecule; transcriptome sequencing; trend

 DESCRIPTION (provided by applicant): Candida albicans is the most frequent causative agent of candidiasis, now the third-to-fourth most common infection in hospitals in the US and worldwide, and this opportunistic fungus represents an increasing threat to an ever expanding population of immune- and medically-compromised patients. Candidiasis carries unacceptably high mortality rates, about 30-60%, clearly indicating that current antifungal therapy is still ineffective, due to the limited armamentarium of antifungal agents, the toxicity displayed by some of the current therapies, and the emergence of resistance to most classes of antifungals. Moreover, there are no new effective drugs in sight, and the antifungal pipeline is mostly dry. The ability to form biofilms, microbial communities attached to surfaces, is intimately linked to the pathogenesis of C. albicans, and indeed the majority of manifestations of candidiasis are associated with biofilm formation, which further complicates treatment. As such biofilm formation represents a high value target for the development of novel antifungals. Most recently, we have carried out high content screens and identified small molecule compounds that specifically inhibit C. albicans biofilm formation. We have been developing some of these compounds as novel antifungals, having confirmed their potent biofilm-inhibitory activity, lack of toxicity and efficacy in vivo using relevant animal models of candidiasis. The main goal of the current project is to further advance the development of the current leading chemical series of compounds, for which we propose three specific objectives. i) Medicinal Chemistry. We will engage on a focused and systematic medicinal chemistry campaign to advance 3-4 structurally diverse lead chemical series in parallel, establish structure- activity relationships that improve biofilm inhibition properties while also improving physical chemical "drug-like" properties. ii) In vivo efficacy. We will test a discrete number of compounds within each chemical series in the murine model of hematogenously disseminated candidiasis, as well as in the murine models of catheter- associated candidiasis and oral candidiasis, both of which are associated with biofilm formation. iii) Insights into mechanisms of action, potential for resistance development, and further in vitro characterization. We will perform further characterization of representative compounds of each chemical series showing the most promise in animal models. These will include RNA-Sequencing and screening of mutant collections to gain insights into the molecular target(-s) and mechanism(-s) of action, serial passage assays to evaluate potential development of resistance, combination with current antifungals, as well as in vitro safety pharmacological profiling for determination of off-target activities.

 描述（由申请人提供）：白色念珠菌是念珠菌病最常见的病原体，目前是美国和全球医院第三至第四常见的感染，这种机会性真菌对不断扩大的人群构成了越来越大的威胁。免疫和医疗受损的患者。念珠菌病具有不可接受的高死亡率，约30- 60%，清楚地表明，目前的抗真菌治疗仍然是无效的，由于有限的抗真菌剂的医疗设备，一些目前的治疗显示的毒性，以及出现耐药性的大多数类别的抗真菌剂。此外，目前还没有新的有效药物，抗真菌药物的管道大多是干燥的。形成生物膜的能力，微生物群落附着在表面，与C的发病机制密切相关。白色念珠菌感染，实际上念珠菌病的大多数表现与生物膜形成有关，这进一步使治疗复杂化。因此，生物膜的形成代表了新型抗真菌药物开发的高价值目标。最近，我们进行了高含量筛选，并确定了特异性抑制C。白色念珠菌生物膜形成。我们已经开发了一些这些化合物作为新的抗真菌药物，已经证实了他们的有效的生物膜抑制活性，缺乏毒性和疗效在体内使用相关的动物模型念珠菌病。当前项目的主要目标是进一步推进当前领先的化学系列化合物的开发，为此我们提出了三个具体目标。i）药物化学。我们将致力于集中和系统的药物化学活动，并行推进3-4个结构多样的先导化学系列，建立结构-活性关系，改善生物膜抑制特性，同时改善物理化学“药物样”特性。ii）体内功效。我们将在血源性播散性念珠菌病的鼠模型以及导管相关念珠菌病和口腔念珠菌病的鼠模型中测试每个化学系列内的离散数量的化合物，这两种模型都与生物膜形成相关。iii）深入了解作用机制、耐药性发展潜力以及进一步的体外表征。我们将对每个化学系列的代表性化合物进行进一步表征，这些化合物在动物模型中表现出最大的希望。这些将包括RNA测序和突变体集合的筛选，以深入了解分子靶标和作用机制，连续传代试验，以评估潜在的耐药性发展，与当前抗真菌药物的组合，以及用于确定脱靶活性的体外安全药理学分析。