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、炎症和病变为特征的阴道感染， 每年影响140万美国女性VVC主要由白色念珠菌引起，白色念珠菌是一种真菌， 响应于微生物组扰动而从寄生酵母形式转变为致病菌丝形式 比如抗生素。虽然抗真菌药物治疗了许多VVC发作，但20%的确诊女性经历了 复发性VVC，这表明保持持久的健康需要恢复保护性阴道 微生物组，而不仅仅是消灭病原体。一个明确的阴道来源的微生物财团可以恢复 微生物组功能丧失-阴道小生境广泛定植和产生真菌抑制剂， 表面活性剂和乳酸，以抵抗随后的C.预防VVC复发。 然而，产生一个最佳的治疗财团需要彻底了解如何 微生物菌株的组合功能，这是微生物学中的一个突出挑战， 仅从宏基因组信息就能回答。高通量筛选（HTS）可以揭示微生物 执行特定期望功能的财团;然而， 构建和测量数以百万计的微生物群落阻碍了该策略的实际应用。协奏曲 Biosciences使用kChip解决了这个问题，kChip是一种新型HTS平台，可以构建和测量约500，000个 确定的微生物组合，并可以利用进行直接的功能测定数百万 在筛选活动期间进行组合。在第一阶段的提案中，Concerto建议执行kChip 筛选阴道来源微生物的10 M多菌株组合，以直接鉴定抑制 C.白色念珠菌生长和菌丝形成，VVC的标志。我们的目标是（1）建立一个细菌菌株的生物库 来源于健康供体的阴道样本，可以形成设计的微生物聚生体的基础，（2） 发展C.在kChip筛选背景下的白色念珠菌生长和菌丝形成，以及 (3)鉴定抑制C.白色念珠菌生长和菌丝形成跨越多个 环境，包括阴道提取物。通过该屏幕确定的顶级财团将接受额外的 发展的主题，未来的第二阶段的建议，以产生一个领先的财团治疗。这 治疗将代表第一个定义，多菌株微生物组恢复治疗妇女的健康 有可能安全有效地改善数百万美国人的复发性VVC。更广泛地说， kChip启动发现的成功实施将推动快速发现其他真菌的治疗方法 （脂溢性皮炎和毛霉菌病）和阴道（细菌性阴道病、早产和STI 传播）疾病。