Small molecule inhibitors of Candida albicans biofilm formation

描述(申请人提供)：念珠菌病目前是美国和全世界第四大最常见的医院感染，白色念珠菌仍然是最常见的念珠菌病病原体。不幸的是，这些感染与令人无法接受的高发病率和死亡率有关。念珠菌病的各种表现与不同类型表面上生物膜的形成有关。生物膜的形成具有重要的后果，因为生物膜中的固着细胞表现出与浮游生物细胞截然不同的表型特征，例如对抗真菌药物的抗性增加和对宿主防御的保护。一旦建立起来，生物膜就有可能引发或延长感染，因为它提供了一个安全的蓄水池，微生物可以从这个蓄水池入侵当地组织，播种新的感染点，或抵制根除努力。净影响是念珠菌生物被膜对这些患者的健康造成不利影响，频率和严重性都在增加，经济后遗症也在飙升。因此，拟议研究的主要目标是设计新的策略来防止白色念珠菌生物被膜的形成。为此，我们将：i)在高通量筛选抑制白色念珠菌生物被膜形成的小分子化合物的基础上，使用基于表型的方法，以及ii)在初始筛选中表征被识别为“HITS”和“LEADS”的选定生物活性分子的生物被膜抑制作用。这些分析利用了本实验室开发的一种简单、快速、稳健、准确和高度重复性的基于微滴度的念珠菌生物被膜形成模型，该模型非常适合自动化和高通量应用。基于小分子的方法提供了强大的手段来解决具有实验挑战性的复杂生物现象，如生物膜的形成，同时确定新的潜在药物开发目标。对公众健康：生物膜的形成对人类健康造成严重后果。这项研究背后的主要思想是，通过消除白色念珠菌形成生物膜的能力，可以大幅降低发病率、死亡率和延长住院时间，同时降低医疗成本。

DESCRIPTION (provided by applicant): Candidiasis represents now the fourth most frequent nosocomial infection in the US and worldwide and C. albicans remains the most frequent causative agent of candidiasis. Unfortunately these infections are associated with unacceptably high morbidity and mortality rates. A variety of manifestations of candidiasis are associated with biofilm formation on the surface of different types of surfaces. Biofilm formation carries important consequences since sessile cells in biofilms display phenotypic traits that are dramatically different from their planktonic counterparts, such as increased resistance to antifungal agents and protection from host defenses. Once established, biofilms have the potential to initiate or prolong infections by providing a safe reservoir from which organisms can invade local tissue, seed new infection sites, or resist eradication efforts. The net effect is that Candida biofilms adversely impact the health of these patients, with increasing frequency and severity, and with soaring economic sequelae. Therefore, the main objective of the proposed studies is to devise novel strategies to prevent C. albicans biofilm formation. To this end we will: i) use a phenotype-based approach based on the high throughput screening for small molecule compounds which inhibit C. albicans biofilm formation, and ii) characterize the biofilm-inhibitory effects of selected bioactive molecules identified as "hits" and "leads" during the initial screens. These assays take advantage of a simple, rapid, robust, accurate and highly reproducible microtiter-based model for the formation of Candida biofilms developed in this laboratory that is ideally suited for automation and high throughput applications. Small-molecule-based approaches provide powerful means to address experimentally challenging and complex biological phenomena, such as biofilm formation, while simultaneously identifying new potential targets for drug development. to public health: Biofilm formation has severe consequences for human health. The main idea behind this study is that by eliminating the ability of C. albicans to form biofilms, a substantial reduction in morbidity, mortality and extended hospital stay can be achieved while simultaneously reducing healthcare costs.