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

用于全身和皮肤耳念珠菌感染的第二代真菌的开发和评估

• 批准号: 10561860
• 负责人: Mahmoud A Ghannoum
• 金额: $ 55.44万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-10 至 2027-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10561860
• 关键词: 5 year old; Address; Affect; Amphotericin B; Animals; Antifungal Agents; Antifungal Therapy; Azoles; Blood - brain barrier anatomy; Brain; Cancer Patient; Candida; Candida albicans; Candida auris; Centers for Disease Control and Prevention (U.S.); Central Nervous System Infections; Classification; Clinical; Collection; Cutaneous; Data; Development; Disseminated candidiasis; Dose; Drug Kinetics; Evaluation; Exhibits; Fermentation; Fluconazole resistance; Flucytosine; Fungal Meningitis; Generations; Geographic Locations; Immunocompromised Host; In Vitro; Individual; Infection; Injections; Innate Immune Response; Kidney Failure; Label; Marketing; Methods; Modality; Modeling; Monitor; Mucous Membrane; Mycoses; Nosocomial Infections; Oral; Oral Examination; Pathogenicity; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Polyenes; Pre-Clinical Model; Predisposition; Property; Protocols documentation; Public Health; Reporting; Resistance; Resistant candida; Resolution; Sepsis; Skin; Skin colonization; Terpenes; Testing; Therapeutic; Toxicology; Transplant Recipients; Work; adaptive immune response; antimicrobial; blood-brain barrier crossing; blood-brain barrier penetration; comparative efficacy; cranium; design; efficacy evaluation; fungicide; guinea pig model; hemiacetal; improved outcome; in vivo; innovation; insight; intravital microscopy; member; mortality; mouse model; novel therapeutics; pathogen; preclinical study; resistant strain; screening; standard of care; therapy development; transmission process

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.

耳念珠菌已成为全球威胁，导致严重的侵袭性感染，死亡率接近 全球近 60%。大多数耳念珠菌感染是院内感染，据报道对 氟康唑 (FLU) 和两性霉素 B (AmB) 对三大类细菌具有不同的耐药性 临床上可用的抗真菌药物（唑类、多烯类、棘白菌素），某些菌株对所有三种药物均具有耐药性 抗真菌类药物，从而限制了治疗选择。耳念珠菌已被列为“新出现的威胁” 尽管白色念珠菌仍然是最常见和最常见的，但疾病控制中心 (CDC) 致病性念珠菌属。耳念珠菌被列为全球紧急威胁，而念珠菌属。和其他 随着抗性真菌物种的出现，需要确定和开发治疗感染的新方法 由念珠菌属引起。由于耳念珠菌定殖于皮肤并充当感染病灶，因此， 一种能够同时靶向皮肤并表现出全身功效的药物将具有高度创新性和 理想的。 一种三萜类抗真菌药，源自 enfumafungin，一种从发酵中分离出来的半缩醛 激素属（一般称为 fungerps），代表第一种新描述的抗真菌药物 自 2001 年起就开始开发化合物。目前，第二代 fungerp SCY-247 正在开发中，作为一种潜在的 全身治疗选择。因为皮肤是耳念珠菌的天然生态位，传播是通过 皮肤接触，表明 SCY-247 除了全身起作用（包括在 血脑屏障），是有效的，因为耳念珠菌的皮肤（即去定植）治疗是创新的。 我们假设我们的全身和皮肤耳念珠菌感染的临床前模型将使我们能够 证明 SCY-247 作为皮肤和播散性感染的新治疗方法的功效 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 SCY-247 对念珠菌抑制/杀菌的有效体外和体内范围 对传统抗真菌治疗具有耐药性的菌株，尤其是耳念珠菌菌株； 2) 雇用 建立了耳念珠菌皮肤豚鼠和小鼠模型来解决治疗和 使用 SCY-247 进行非殖民化方法，最后； 3) 确定 SCY-247 在 治疗由耳念珠菌或白色念珠菌引起的中枢神经系统（CNS）感染。使用一个 颅内小鼠模型和高分辨率活体显微镜（IVM）。顺利完成这些 目标将确定 SCY-247 是否是根除耳念珠菌的可行选择，以及该化合物是否 对已知的耐药念珠菌属有效。我们将评估口服和静脉注射。 SCY-247的剂量 比较它们的潜在功效。最后，将评估 SCY-247 治疗耳念珠菌脑部感染的能力。 这些临床前研究的成功完成将使 SCY-247 进入 1 期临床试验。