Department of Biology and South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, Texas, USA.
Department of Biology, University of the Incarnate Word, San Antonio, Texas, USA.
mBio. 2017 Dec 5;8(6):e01991-17. doi: 10.1128/mBio.01991-17.
remains the main etiologic agent of candidiasis, the most common fungal infection and now the third most frequent infection in U.S. hospitals. The scarcity of antifungal agents and their limited efficacy contribute to the unacceptably high morbidity and mortality rates associated with these infections. The yeast-to-hypha transition represents the main virulence factor associated with the pathogenesis of infections. In addition, filamentation is pivotal for robust biofilm development, which represents another major virulence factor for candidiasis and further complicates treatment. Targeting pathogenic mechanisms rather than growth represents an attractive yet clinically unexploited approach in the development of novel antifungal agents. Here, we performed large-scale phenotypic screening assays with 30,000 drug-like small-molecule compounds within ChemBridge's DIVERSet chemical library in order to identify small-molecule inhibitors of filamentation, and our efforts led to the identification of a novel series of bioactive compounds with a common biaryl amide core structure. The leading compound of this series, -[3-(allyloxy)-phenyl]-4-methoxybenzamide, was able to prevent filamentation under all liquid and solid medium conditions tested, suggesting that it impacts a common core component of the cellular machinery that mediates hypha formation under different environmental conditions. In addition to filamentation, this compound also inhibited biofilm formation. This leading compound also demonstrated activity in clinically relevant murine models of invasive and oral candidiasis. Overall, our results indicate that compounds within this series represent promising candidates for the development of novel anti-virulence approaches to combat infections. Since fungi are eukaryotes, there is a limited number of fungus-specific targets and, as a result, the antifungal arsenal is exceedingly small. Furthermore, the efficacy of antifungal treatment is compromised by toxicity and development of resistance. As a consequence, fungal infections carry high morbidity and mortality rates, and there is an urgent but unmet need for novel antifungal agents. One appealing strategy for antifungal drug development is to target pathogenetic mechanisms associated with infection. In , one of the most common pathogenic fungi, morphogenetic transitions between yeast cells and filamentous hyphae represent a key virulence factor associated with the ability of fungal cells to invade tissues, cause damage, and form biofilms. Here, we describe and characterize a novel small-molecule compound capable of inhibiting filamentation both and ; as such, this compound represents a leading candidate for the development of anti-virulence therapies against candidiasis.
白色念珠菌仍然是念珠菌病的主要病因，念珠菌病是最常见的真菌感染，现在也是美国医院中第三常见的感染。抗真菌药物的稀缺性及其有限的功效导致与这些感染相关的发病率和死亡率高得令人无法接受。酵母到菌丝的转变代表了与感染发病机制相关的主要毒力因素。此外，菌丝形成对于稳健的生物膜发育至关重要，生物膜发育是念珠菌病的另一个主要毒力因素，进一步使治疗复杂化。针对致病机制而不是生长代表了开发新型抗真菌药物中一种有吸引力但尚未在临床上得到利用的方法。在这里，我们使用 ChemBridge 的 DIVERSet 化学文库中的 30000 种药物样小分子化合物进行了大规模表型筛选实验，以鉴定白色念珠菌菌丝形成的小分子抑制剂，我们的努力导致了具有共同联苯酰胺核心结构的新型生物活性化合物系列的鉴定。该系列的领先化合物 -[3-(丙烯氧基)-苯基]-4-甲氧基苯甲酰胺，能够在所有测试的液体和固体培养基条件下阻止菌丝形成，这表明它影响了介导不同环境条件下菌丝形成的细胞机制的共同核心组件。除了菌丝形成，这种化合物还抑制了生物膜的形成。这种先导化合物在临床上相关的侵袭性和口腔念珠菌病的小鼠模型中也表现出活性。总的来说，我们的结果表明，该系列中的化合物代表了开发新型抗毒力方法来对抗白色念珠菌感染的有希望的候选物。由于真菌是真核生物，因此真菌特异性靶标数量有限，因此抗真菌武器库非常小。此外，抗真菌治疗的疗效受到毒性和耐药性的影响。因此，真菌感染的发病率和死亡率很高，迫切需要但尚未满足开发新型抗真菌药物的需求。抗真菌药物开发的一种有吸引力的策略是针对与感染相关的发病机制。在白色念珠菌中，酵母细胞和丝状菌丝之间的形态发生转换是与真菌细胞侵袭组织、造成损伤和形成生物膜的能力相关的主要毒力因素之一。在这里，我们描述并表征了一种能够抑制白色念珠菌和菌丝形成的新型小分子化合物；因此，这种化合物是开发抗念珠菌病的抗毒力疗法的主要候选物。
