Development and evaluation of a second-generation fungerp for systemic and cutaneous C. auris infection

金黄色念珠菌已成为一种全球威胁，导致严重的侵袭性感染，死亡率接近 全球近60%的人。大多数金黄色葡萄球菌感染是医院内的，据报道对 氟康唑(Flu)和两性霉素B(Amb)对三个主要类别的成员具有可变耐药性 临床上可用的抗真菌药物(氮唑、多烯、棘球菌素)，有些菌株对这三种药物都有抗药性 抗真菌类药物，从而限制了治疗选择。C.Auris已被归类为“新兴威胁” 根据疾病控制中心(CDC)的报告，尽管白色念珠菌仍然是最常见的和 致病假丝酵母菌。金黄色念珠菌被列为全球紧急威胁，念珠菌属。及其他 随着抗药性真菌品种的出现，有必要确定和开发新的治疗感染的方法 由念珠菌引起。因为金黄色葡萄球菌定植在皮肤上，并作为感染的核心，发展 一种可以同时针对皮肤和显示全身疗效的药物将具有高度的创新性和 令人向往。 一种三萜类抗真菌药物，来自恩福马芬净，一种从发酵中分离出来的半缩醛 霍莫尼玛属(Hormonema Spp)(一般称为真菌)，代表了第一类新描述的抗真菌药物 自2001年以来的化合物。目前，第二代底盘SCY-247正在开发中，作为潜在的 全身治疗选择。因为皮肤是金黄色葡萄球菌的天然生态位，通过 皮肤接触，表明SCY-247除了系统工作外(包括在 血脑屏障)，是一种有效的皮肤(即非殖民化)治疗方法。 我们假设我们的全身和皮肤感染金黄色葡萄球菌的临床前模型将允许我们 证明SCY-247作为一种治疗皮肤和播散性感染的新疗法的有效性 包括脑部感染。因此，我们的多管齐下的方法包括三个具体目标，旨在：1) 确定对念珠菌有抑制/杀菌作用的SCY-247的体内外有效范围 对传统抗真菌治疗耐药的菌株，重点是金黄色葡萄球菌菌株；以及2)使用 建立豚鼠和小鼠皮肤金黄色葡萄球菌模型 使用SCY-247的非殖民化方法，并最终；3)确定SCY-247在 金黄色葡萄球菌或白色念珠菌致中枢神经系统感染的治疗使用 小鼠颅内模型和高分辨率活体显微镜(IVM)。成功完成这些任务 AIMS将确定SCY-247是否是根除金黄色葡萄球菌的可行选择，以及这种化合物是否 对已知的耐药念珠菌有效。我们将评估SCY-247的口服和静脉剂量 比较它们的潜在疗效。最后，将评估SCY-247治疗金黄色葡萄球菌脑感染的能力。 这些临床前研究的成功完成将使SCY-247进入第一阶段临床试验。

Candida auris has emerged as a global threat causing serious invasive infections with mortality approaching nearly 60 percent worldwide. The majority of C. auris infections are nosocomial and reportedly resistant to fluconazole (FLU) and amphotericin B (AmB) with variable resistance to members of the three major classes of clinically available antifungals (azoles, polyenes, echinocandins), with some strains resistant to all three antifungal classes, thereby limiting treatment options. C. auris has been classified as a ‘newly emerging threat’ by the Centers for Disease Control (CDC), although Candida albicans remains the most prevalent and pathogenic Candida species. With C. auris classified as a global urgent threat, and Candida spp. and other resistant fungal species emerging, there is a need to identify and develop new modalities to treat infections caused by Candida spp. Because C. auris colonizes the skin and acts as a nidus of infection, developing a drug that can concurrently target skin and exhibit systemic efficacy will be highly innovative and desirable. A triterpenoid class of antifungals derived from enfumafungin, a hemiacetal isolated from fermentation of Hormonema spp. (generically termed fungerps), represents the first newly described class of antifungal compounds since 2001. Currently, a second-generation fungerp, SCY-247, is under development as a potential systemic therapeutic option. Because the skin is a natural niche for C. auris, and transmission occurs through cutaneous contact, demonstrating that SCY-247, in addition to working systemically (including at the blood brain barrier), is effective as a cutaneous (i.e., decolonization) treatment for C. auris is innovative. We hypothesize that our preclinical models of systemic and cutaneous C. auris infection, will allow us to demonstrate the efficacy of SCY-247 as a new therapeutic treatment for skin as well as disseminated infection including brain infection. Thus, our multi-pronged approach includes three specific aims designed to: 1) Determine the effective in vitro and in vivo range of SCY-247 that is inhibitory/fungicidal to Candida strains resistant to traditional antifungal therapy with an emphasis on C. auris strains; and 2) Employ established cutaneous guinea pig and murine models of C. auris to address treatment and decolonization approaches using SCY-247, and finally; 3) Determine the efficacy of SCY-247 in the treatment of central nervous system (CNS) infection caused by C. auris or C. albicans spp. using an intracranial murine model and high-resolution intravital microscopy (IVM). Successful completion of these aims will determine whether SCY-247 is a viable option for eradication of C. auris, and whether this compound is effective against known resistant Candida spp. We will evaluate both oral and I.V. dosing of SCY-247 comparing their potential efficacy. Finally, the ability of SCY-247 to treat C. auris brain infection will be assessed. Successful completion of these preclinical studies will enable advancing SCY-247 into Phase 1 clinical trials.