Targeting virulence against oral candidiasis in HIV/AIDS

针对艾滋病毒/艾滋病口腔念珠菌病的毒力

基本信息

批准号：
8629722
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
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8629722
关键词：
AIDS/HIV problem Acquired Immunodeficiency Syndrome Antibiotics Antifungal Agents Antifungal Therapy Azole resistance Biological Preservation Candida Candida albicans Candidiasis Cell Survival Cells Clinical Collection Complex Development Drug resistance Ecology Equilibrium Evolution Exhibits Filament Fungal Drug Resistance Growth HIV HIV Infections HIV Seropositivity Health Care Costs Highly Active Antiretroviral Therapy Human Immune response Immunologics In Vitro Individual Infection Laboratories Lead Link Microbial Biofilms Modeling Molecular Molecular Epidemiology Morbidity - disease rate Mus NRG1 gene Natural History Opportunistic Infections Oral Oral Manifestations Oral candidiasis Oral cavity Oral mucous membrane structure Pathogenesis Patients Pharmaceutical Preparations Population Prevention Prevention approach Process Reporting Resistance Resistance development Resources Role Serial Passage Series Surface Tetanus Helper Peptide Time Toxic effect Virulence Virulence Factors Work Yeasts cell growth fungus in vitro Model in vitro activity in vitro testing in vivo insight microbial community microbiome mouse model novel novel strategies oral cavity epithelium oral infection oropharyngeal thrush pathogen pressure public health relevance reconstitution research study response small molecule transcriptomics

项目摘要

DESCRIPTION (provided by applicant): Oral manifestations are widely regarded as important markers of the natural history and progression HIV infection and AIDS. Interestingly, already from the very early reports, one of the AIDS-defining opportunistic infections was oropharyngeal candidiasis (OPC) or thrush. Even in the post-HAART (Highly Active Antiretroviral Therapy) era, OPC still remains one of the most common AIDS defining illnesses and the most common opportunistic oral infection in HIV positive individuals. In HIV-infected patients, the opportunistc pathogenic fungus C. albicans is responsible for the majority of OPC episodes, as this otherwise normal commensal takes advantage of the underlying immunesuppression. Current antifungal therapy for the treatment of OPC has many shortcomings, due to the limited armamentarium of antifungal agents, the toxicity displayed by some of the current therapies and, principally, the emergence of resistance to most classes of antifungals. As conventional antifungal agents target processes that are essential for growth, they impose a high degree of selective pressure and the evolution of resistance is unavoidable. Indeed, resistance has been documented for all clinically used antifungal agents. Targeting pathogenetic mechanisms rather than essential processes represents a very attractive alternative for the development of new antibiotics. C. albicans virulence during oral infection is intimately linked to its ability to undergo morphogenetc conversion (filamentation) and to form biofilms. Thus, we surmise that filamentation and biofilm formation represent high value targets, yet clinically unexploited, for the development of novel anti-virulence approaches for the prevention and treatment of oral candidiasis. We have carried out high content screens and identified small molecule compounds that specifically inhibit C. albicans biofilm formation and filamentation. This application uses our leading compound identified during these screens - for which we have already confirmed lack of toxicity and potent in vivo activity - to fully validate inhibition of filamentation and biofilm formation as alternatie targets for the development of a novel anti-virulence approach against oral candidiasis, for which we will i) further characterize the in vitro activity of our lead anti-virulence compound, wih emphasis on minimizing the potential to induce resistance, ii) determine its in vivo activity in a mouse model of oral candidiasis, iii) determine the impact of treatment with our lead compound in the host immune responses during oral candidiasis, and iv) characterize its mechanism(- s) of action at the molecular level.

描述（由申请人提供）：口服表现被广泛认为是自然病史和进展HIV感染和艾滋病的重要标志。有趣的是，从早期的报告中，定义的机会感染之一是口咽念珠菌病（OPC）或鹅口疮。即使在Haart后（高度活跃的抗逆转录病毒疗法）时代，OPC仍然仍然是定义疾病的最常见艾滋病之一，也是HIV阳性个体中最常见的机会性口腔感染。在感染HIV的患者中，机会症的致病真菌C.白色念珠菌造成了大多数OPC发作，因为这种正常的共生利用了基本的免疫抑制。当前用于OPC治疗的抗真菌疗法由于抗真菌剂的武器群有限，因此某些当前疗法表现出的毒性，并且主要是对大多数抗真菌类别类型的抗性的出现，因此具有许多缺点。由于常规的抗真菌剂对生长必不可少的靶向过程，它们施加了高度的选择性压力和抗性的演变是不可避免的。实际上，已经记录了所有临床使用的抗真菌药物的耐药性。靶向致病机制而不是基本过程是开发新抗生素的一种非常有吸引力的替代方法。在口腔感染期间，白色念珠菌的毒力与其经历形态学转化率（细丝）和形成生物膜的能力密切相关。因此，我们推测，丝和生物膜的形成代表了高价值靶标，但在临床上没有开发，用于开发用于预防和治疗口服念珠菌病的新型抗病毒方法。我们已经进行了高含量筛选，并确定了专门抑制白色念珠菌生物膜形成和细丝的小分子化合物。该应用使用在这些筛选期间鉴定出的主要化合物（我们已经确认缺乏毒性和体内活性的有效性），充分验证对丝状和生物膜形成的抑制作用，作为开发一种新型抗病毒式方法对口腔群体开发的替代目标，这将进一步表征我们的最小及其在体外的特征。诱导抗性，ii）确定其在口服念珠菌病小鼠模型中的体内活性，iii）确定在口服念珠菌病期间宿主免疫反应中使用铅化合物的治疗的影响，而iv）则表征了其在分子水平上作用的机制（ - s）。