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.

耳念珠菌已成为一种全球性的威胁，造成严重的侵袭性感染，死亡率接近 全球近60%。大多数C.耳感染是医院感染，据报道对 氟康唑（FLU）和阿替霉素B（AmB）对三种主要的 临床上可用的抗真菌药（唑类、多烯类、棘白菌素类），一些菌株对所有三种药物均耐药 抗真菌类，从而限制了治疗选择。C. auris已被列为“新出现的威胁” 由疾病控制中心（CDC），虽然白色念珠菌仍然是最普遍的， 致病念珠菌属。梭被列为全球紧急威胁的耳念珠菌和念珠菌属（Candida spp.）和其他 随着耐药真菌物种的出现，需要鉴定和开发新的治疗感染的方式 由念珠菌属（Candida spp.）因为C.耳寄生在皮肤上，充当感染病灶，发展 能够同时靶向皮肤并表现出全身功效的药物将是高度创新的， 令人向往 一种三萜类抗真菌药，来源于恩福马芬净，恩福马芬净是一种半缩醛， 激素丝菌属（一般称为fungerps），代表了第一类新描述的抗真菌药物 自2001年以来，化合物。目前，第二代真菌SCY-247正在开发中， 全身治疗选择。因为皮肤是C的天然利基。耳，并通过传播发生 皮肤接触，表明SCY-247，除了工作全身（包括在 血脑屏障），作为皮肤（即，非殖民化）处理C.奥瑞思是创新的。 我们假设我们的全身和皮肤C.耳道感染，可以让我们 证明SCY-247作为一种新的皮肤和播散性感染的治疗方法的有效性 包括脑部感染因此，我们多管齐下的方法包括三个具体目标，旨在： 确定SCY-247对念珠菌的抑制/杀真菌作用的体外和体内有效范围 对传统抗真菌治疗耐药的菌株，重点是C. auris菌株;和2）使用 建立了豚鼠和小鼠皮肤C.耳治疗， 使用SCY-247的去殖民化方法，最后; 3）确定SCY-247在 治疗由C. auris或C.白色念珠菌属使用 颅内鼠模型和高分辨率活体显微镜（IVM）。成功完成这些 目的将决定SCY-247是否是根除C.耳，以及这种化合物是否 对已知耐药念珠菌属有效。我们将评估SCY-247的口服和静脉给药 比较其潜在功效。最后，SCY-247治疗C.将评估耳脑感染。 这些临床前研究的成功完成将使SCY-247进入1期临床试验。