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.

念珠菌的Auris已成为一种全球威胁，导致严重的侵入性感染，死亡率接近 全球近60％。大多数奥氏梭菌感染是医院的，据报道 氟康唑（流感）和两性霉素B（AMB）具有对三个主要类别的成员的耐药性 临床上可用的抗真菌剂（唑，多烯，echinocandins），对这三种菌株具有抗性 抗真菌类，从而限制治疗选择。 C. Auris被归类为“新出现的威胁” 由疾病控制中心（CDC），尽管白色念珠菌仍然是最普遍的，并且 致病性念珠菌。 C. Auris归类为全球紧急威胁，而Candida SPP。还有其他 抗性真菌物种出现，有必要识别和发展新的方式来治疗感染 由念珠菌属引起。因为C. auris在皮肤上殖民并充当感染的nidus 可以同时靶向皮肤和暴露全身效率的药物将是高度创新的，并且 理想。 源自Enfumafungin的三萜类抗真菌剂，这是一种从发酵 激素属。 （通常称为fungerps），代表了第一个新描述的抗真菌类 自2001年以来的化合物。目前，第二代SCY-247正在开发中，这是一种潜力 全身治疗选择。因为皮肤是C. auris的天然利基市场，并且通过 皮肤接触，表明SCY-247除了系统地工作（包括在 血脑屏障），作为一种对Auris的皮肤（即非殖民化）治疗有效的是创新的。 我们假设我们的全身性和皮肤梭菌感染的临床前模型将使我们能够 证明SCY-247作为皮肤和传播感染的新治疗疗法的效率 包括大脑感染。这就是我们的多种方法包括三个旨在：1）的特定目标 确定抑制性/杀真菌念珠菌的SCY-247的有效体外和体内范围 对传统抗真菌疗法的抗菌菌株，重点是Auris菌株； 2）雇用 已建立的皮肤巨猪和小梭状芽孢杆菌的鼠模型，以解决治疗和 非殖民化使用SCY-247，最后是； 3）确定SCY-247在 由C. auris或白色念珠菌属引起的中枢神经系统（CNS）感染的治疗。使用一个 颅内鼠模型和高分辨率浸润显微镜（IVM）。这些成功完成 AIMS将确定SCY-247是否是C. Auris辐射的可行选择，以及该化合物是否 有效防止已知的抗性念珠菌属。我们将评估口头和i.v. SCY-247的剂量 比较它们的潜在有效性。最后，将评估SCY-247治疗Auris脑感染的能力。 这些临床前研究的成功完成将使SCY-247能够进入1阶段临床试验。