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
基本信息
- 批准号:10561860
- 负责人:
- 金额:$ 55.44万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:5 year oldAddressAffectAmphotericin BAnimalsAntifungal AgentsAntifungal TherapyAzolesBlood - brain barrier anatomyBrainCancer PatientCandidaCandida albicansCandida aurisCenters for Disease Control and Prevention (U.S.)Central Nervous System InfectionsClassificationClinicalCollectionCutaneousDataDevelopmentDisseminated candidiasisDoseDrug KineticsEvaluationExhibitsFermentationFluconazole resistanceFlucytosineFungal MeningitisGenerationsGeographic LocationsImmunocompromised HostIn VitroIndividualInfectionInjectionsInnate Immune ResponseKidney FailureLabelMarketingMethodsModalityModelingMonitorMucous MembraneMycosesNosocomial InfectionsOralOral ExaminationPathogenicityPatientsPharmaceutical PreparationsPhase I Clinical TrialsPolyenesPre-Clinical ModelPredispositionPropertyProtocols documentationPublic HealthReportingResistanceResistant candidaResolutionSepsisSkinSkin colonizationTerpenesTestingTherapeuticToxicologyTransplant RecipientsWorkadaptive immune responseantimicrobialblood-brain barrier crossingblood-brain barrier penetrationcomparative efficacycraniumdesignefficacy evaluationfungicideguinea pig modelhemiacetalimproved outcomein vivoinnovationinsightintravital microscopymembermortalitymouse modelnovel therapeuticspathogenpreclinical studyresistant strainscreeningstandard of caretherapy developmenttransmission process
项目摘要
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Mahmoud A Ghannoum其他文献
Time to Think Antifungal Resistance Increased Antifungal Resistance Exacerbates the Burden of Fungal Infections Including Resistant Dermatomycoses
是时候考虑抗真菌耐药性了 抗真菌耐药性的增加会加剧包括耐药性皮肤真菌病在内的真菌感染的负担
- DOI:
- 发表时间:
2024 - 期刊:
- 影响因子:0
- 作者:
Thomas S McCormick;Mahmoud A Ghannoum - 通讯作者:
Mahmoud A Ghannoum
Mahmoud A Ghannoum的其他文献
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{{ truncateString('Mahmoud A Ghannoum', 18)}}的其他基金
Polymicrobial interactions in Crohn's Disease
克罗恩病中的多种微生物相互作用
- 批准号:
10441347 - 财政年份:2019
- 资助金额:
$ 55.44万 - 项目类别:
Polymicrobial interactions in Crohn's Disease
克罗恩病中的多种微生物相互作用
- 批准号:
9973148 - 财政年份:2019
- 资助金额:
$ 55.44万 - 项目类别:
Polymicrobial interactions in Crohn's Disease
克罗恩病中的多种微生物相互作用
- 批准号:
10652329 - 财政年份:2019
- 资助金额:
$ 55.44万 - 项目类别:
Polymicrobial interactions in Crohn's Disease
克罗恩病中的多种微生物相互作用
- 批准号:
10223109 - 财政年份:2019
- 资助金额:
$ 55.44万 - 项目类别:
Mechanism of antifungal action of Pichia proteins
毕赤酵母蛋白的抗真菌作用机制
- 批准号:
8821602 - 财政年份:2014
- 资助金额:
$ 55.44万 - 项目类别:
Mechanism of antifungal action of Pichia proteins
毕赤酵母蛋白的抗真菌作用机制
- 批准号:
9422694 - 财政年份:2014
- 资助金额:
$ 55.44万 - 项目类别:
Mechanism of antifungal action of Pichia proteins
毕赤酵母蛋白的抗真菌作用机制
- 批准号:
8996475 - 财政年份:2014
- 资助金额:
$ 55.44万 - 项目类别:
Mechanism of antifungal action of Pichia proteins
毕赤酵母蛋白的抗真菌作用机制
- 批准号:
8671094 - 财政年份:2014
- 资助金额:
$ 55.44万 - 项目类别:
Identification of early phase C. albicans biofilm proteins
早期白色念珠菌生物膜蛋白的鉴定
- 批准号:
8063533 - 财政年份:2007
- 资助金额:
$ 55.44万 - 项目类别:
Identification of early phase C. albicans biofilm proteins
早期白色念珠菌生物膜蛋白的鉴定
- 批准号:
7424061 - 财政年份:2007
- 资助金额:
$ 55.44万 - 项目类别:
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