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。
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:
8671094 - 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:
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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