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（由适用提供）：白色念珠菌是念珠菌最常见的念珠菌药物，现在是美国和全球医院中第三到四分之一最常见的感染，这种机会主义的真菌代表了对不断扩大的免疫和医学良性和医疗保障患者的越来越多的威胁。念珠菌的死亡率高约30-60％，这清楚地表明，由于抗真菌药物的武器有限，当前某些疗法表现出的毒性以及对大多数类抗真菌药的抗药性的出现所表现出的毒性，目前的抗真菌疗法仍然无效。此外，看不到新的有效药物，抗真菌管道大多是干燥的。形成生物膜，附着在表面上的微生物群落的能力与白色念珠菌的发病机理密切相关，实际上，念珠菌病的大部分表现与生物膜的形成有关，这进一步使治疗复杂化。由于这种生物膜的形成代表了新型抗真菌剂的发展的高价值靶标。最近，我们进行了高含量筛选，并确定了专门抑制白色念珠菌生物膜形成的小分子化合物。我们一直在使用相关动物确认其潜在的抑制活性，在体内缺乏毒性和效率，目前项目的主要目标是进一步推动当前领先的化学化合物的主要目标，为此我们提出了三个特定的对象。 i）药物化学。我们将参与一项重点和系统的医学化学运动，以同时发展3-4个结构上不同的铅化学系列，建立结构活性关系，以改善生物膜抑制特性，同时也改善了物理化学“类似药物”的特性。 ii）体内效率。我们将在血源性散布念珠菌病的鼠模型以及导管 - 相关的念珠菌病和口服念珠菌病的鼠模型中测试每个化学系列中的分散数量，这两者都与生物膜形成有关。 iii）深入了解作用机理，耐药性发展的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，显示动物模型中最有望的。这些将包括对突变体收集的RNA测序和筛选，以洞悉动作的分子靶标（-s）和机制（-s），串行通道评估，以评估电阻的潜在发展，与当前的抗真菌性的结合以及体外安全性药物分析，以确定不及要素活动。