Discovery of bacterial consortia to treat recurrent vulvovaginal candidiasis: a generalizable platform for phenotypic microbial community screening

发现治疗复发性外阴阴道念珠菌病的细菌群落：表型微生物群落筛查的通用平台

• 批准号: 10383360
• 负责人: Jared Scott Kehe
• 金额: $ 29.99万
• 依托单位: CONCERTO BIOSCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10383360
• 关键词: Affect; American; Antibiotics; Antifungal Agents; Atopobium vaginae; Automobile Driving; Bacteria; Bacterial Vaginosis; Behavior; Biological Assay; Biological Sciences; Candida; Candida albicans; Carbon; Communicable Diseases; Complex; Consumption; Cutaneous Candidiasis; Data; Development; Diagnosis; Disease; Economic Burden; Effectiveness; Environment; Explosion; Folliculitis; Future; Goals; Grant; Growth; Health; Human; Hyphae; Impairment; In Vitro; Inflammation; Inflammatory; Knowledge; Lactic acid; Lead; Legal patent; Lesion; Libraries; Liquid substance; Logistics; Malassezia; Malignant Neoplasms; Measures; Mediating; Metabolic; Metagenomics; Methods; Microbe; Microbiology; Morphology; Mucormycosis; Onychomycosis; Optics; Pain; Pathogenicity; Phase; Phenotype; Premature Birth; Problem Solving; Production; Property; Pruritus; Quality of life; Recurrence; Resources; Sampling; Seborrheic dermatitis; Source; Technology; Therapeutic; Training; Vagina; Virulence; Virulent; Vulvovaginal Candidiasis; Woman; Women' s Health; Work; Yeasts; base; biobank; clinical development; combinatorial; convolutional neural network; design; detection method; experience; feature detection; fungus; high throughput screening; inhibitor; innovation; intimate behavior; microbial; microbial community; microbiome; microbiome alteration; microbiota; nanolitre; novel; pathogen; plant growth/development; prevent; reduce symptoms; response; restoration; screening; success; surfactant; therapeutic development; transmission process; vaginal infection; vaginal microbiome

Vulvovaginal candidiasis (VVC), a vaginal infection characterized by vulval itching, inflammation, and lesions, affects 1.4 million American women per year. VVC is primarily caused by Candida albicans, a fungus that switches from a commensal yeast form to a pathogenic hyphal form in response to microbiome perturbations such as antibiotics. While antifungals treat many VVC episodes, 20% of diagnosed women experience recurrent VVC, suggesting that maintaining long-lasting health requires restoration of a protective vaginal microbiome, not just eradication of a pathogen. A defined consortium of vaginal-derived microbes could restore lost microbiome functions—broad colonization of vaginal niches and production of fungal inhibitors such as surfactants and lactic acid—to resist subsequent blooms of C. albicans and prevent recurrent VVC. Nevertheless, generating an optimal therapeutic consortium requires a thorough understanding of how microbial strains function in combination, an outstanding challenge in microbiology that cannot yet be answered from metagenomic information alone. High-throughput screening (HTS) could reveal microbial consortia that perform specific desirable functions; however, the complex liquid handling necessary to construct and measure millions of microbial communities has prevented practical use of this strategy. Concerto Biosciences solves this problem using kChip, a novel HTS platform that can construct and measure ~500,000 defined microbial combinations per day, and can be leveraged to perform direct functional assays of millions of combinations during a screening campaign. In this Phase I proposal, Concerto proposes to perform a kChip screen of 10M multistrain combinations of vaginal-derived microbes to directly identify consortia that suppress C. albicans growth and hyphae formation, hallmarks of VVC. We aim to (1) build a biobank of bacterial strains derived from healthy donors’ vaginal samples that can form the basis of designed microbial consortia, (2) develop quantitative measures of C. albicans growth and hyphae formation in a kChip screening context, and (3) identify strain combinations that suppress C. albicans growth and hyphae formation across multiple environments, including vaginal extracts. The top consortia identified by this screen will undergo additional development—the subject of a future Phase II proposal—to generate a lead consortium therapeutic. This therapeutic will represent the first defined, multistrain microbiome restoration therapeutic in women’s health with the potential to safely and effectively ameliorate recurrent VVC of millions of Americans. More broadly, successful implementation of kChip-enabled discovery will fuel rapid discovery of treatments for other fungal (seborrheic dermatitis and mucormycosis) and vaginal (bacterial vaginosis, preterm birth, and STI transmission) diseases.

外阴阴道念珠菌病（VVC），一种以外阴瘙痒，感染和病变为特征的阴道感染， 每年影响140万美国妇女。 VVC主要是由白色念珠菌引起的，它是一种真菌 响应微生物组扰动，从共生酵母形式转换为致病性菌丝形式 例如抗生素。抗真菌师治疗许多VVC发作，而20％的诊断女性经历 复发性VVC，表明保持长期健康需要恢复受保护的阴道 微生物组，不仅是病原体的辐射。固定的阴道衍生微生物联盟可以恢复 微生物组功能丢失 - 阴道壁ches的殖民化和真菌抑制剂的产生，例如 表面活性剂和乳酸 - 可抵抗白色念珠菌的随后血液并防止复发性VVC。 然而，产生一个最佳的治疗联盟需要彻底了解 微生物菌株的功能结合起来，这是微生物学的出色挑战 仅从宏基因组信息回答。高通量筛查（HTS）可能揭示微生物 执行特定理想功能的联盟；但是，复杂的液体处理需要 构建和衡量数百万个微生物群落已经阻止了这种策略的实际使用。协奏曲 Biosciences使用Kchip（可以构建和测量约500,000的新型HTS平台Kchip解决此问题 每天定义的微生物组合，可以利用以执行数百万的直接功能测定 筛选活动期间的组合。在此阶段我的建议中，协奏曲提出了执行Kchip的建议 阴道衍生微生物的1000万层组合的屏幕，以直接识别抑制的财团 C.白色念珠菌生长和菌丝形成，VVC的标志。我们的目标是（1）建立细菌菌株的生物库 源自健康供体的阴道样本，可以构成设计的微生物联盟的基础，（2） 在Kchip筛查环境中制定白色念珠菌生长和菌丝形成的定量测量，以及 （3）确定抑制白色念珠菌生长和菌丝形成的应变组合 环境，包括阴道提取物。此屏幕确定的顶级财团将遭受其他 开发（未来II期提议的主题）生成铅财团治疗。这 治疗方法将代表女性健康中的第一个定义的多层铅微生物组修复疗法 有可能安全有效地改善数百万美国人的复发性VVC。更广泛地 成功实施Kchip启用了基于Kchip的发现将促进其他真菌的治疗方法 （脂肪性皮炎和粘膜菌病）和阴道（细菌性阴道化，早产和STI 传播）疾病。