Targeting virulence against oral candidiasis in HIV/AIDS

描述（由申请人提供）：口腔表现被广泛认为是HIV感染和AIDS自然史和进展的重要标志。有趣的是，从早期的报告中，艾滋病定义的机会性感染之一是口咽念珠菌病（OPC）或鹅口疮。即使在后HAART（高效抗逆转录病毒疗法）时代，OPC仍然是最常见的艾滋病定义疾病之一，也是HIV阳性个体中最常见的机会性口腔感染。在HIV感染者中，机会致病真菌C.白念珠菌是大多数OPC发作的原因，因为这种正常的细胞利用了潜在的免疫抑制。目前用于治疗OPC的抗真菌疗法具有许多缺点，这是由于抗真菌剂的设备有限、一些当前疗法所显示的毒性以及主要是对大多数类别的抗真菌剂的耐药性的出现。由于传统的抗真菌剂靶向生长所必需的过程，它们施加了高度的选择压力，并且耐药性的演变是不可避免的。事实上，所有临床使用的抗真菌药物都有耐药性记录。靶向致病机制而不是基本过程是开发新抗生素的一个非常有吸引力的选择。C.白色念珠菌在口腔感染期间的毒力与其经历形态发生转化（变形）和形成生物膜的能力密切相关。因此，我们认为，细菌的形成和生物膜的形成是高价值的目标，但临床上尚未开发，用于预防和治疗口腔念珠菌病的新的抗毒力的方法的发展。我们已经进行了高含量的筛选，并确定了特异性抑制C。白色念珠菌生物膜形成和粘附。本申请使用在这些筛选期间鉴定的我们的先导化合物-我们已经证实其缺乏毒性和有效的体内活性-以充分验证对细菌形成和生物膜形成的抑制作为开发针对口腔念珠菌病的新型抗毒力方法的替代靶标，为此，我们将i）进一步表征我们的先导抗毒力化合物的体外活性，重点在于使诱导抗性的可能性最小化，i i）确定其在口腔念珠菌病小鼠模型中的体内活性，iii）确定在口腔念珠菌病期间用我们的先导化合物治疗对宿主免疫应答的影响，和iv）在分子水平上表征其作用机制。

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.