Development of novel chemical series of Candida albicans biofilm inhibitors
白色念珠菌生物膜抑制剂新型化学系列的开发
基本信息
- 批准号:8951343
- 负责人:
- 金额:$ 36.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-06-22 至 2020-05-31
- 项目状态:已结题
- 来源:
- 关键词:Action PotentialsAdvanced DevelopmentAnimal ModelAnti-Bacterial AgentsAntibioticsAntifungal AgentsAntifungal TherapyBiologicalBiological AssayBiologyCandida albicansCandidiasisCathetersChemical StructureChemicalsCollectionCommunicable DiseasesDevelopmentDisseminated candidiasisFeedbackGoalsHealth Care CostsHospitalsImmuneIn VitroIncidenceInfectionLeadLinkMicrobial BiofilmsMicrobiologyModelingMolecular TargetMorbidity - disease rateMusMycosesNatureOral candidiasisPathogenesisPatientsPharmaceutical ChemistryPharmaceutical PreparationsPopulationPreventionProcessPropertyRNA SequencesResearch PersonnelResistanceResistance developmentSafetySerial PassageSeriesStructure-Activity RelationshipSurfaceTestingTimeToxic effectVisionanalogcandidemiachemical propertyclinically relevantcostdesigndrug developmentfungushigh riskimprovedin vivoinhibitor/antagonistinnovationinsightlead seriesmicrobial communitymortalitymutantnovelnovel strategiespreclinical studypublic health relevanceresearch studyscreeningsmall moleculetranscriptome sequencingtrend
项目摘要
DESCRIPTION (provided by applicant): Candida albicans is the most frequent causative agent of candidiasis, now the third-to-fourth most common infection in hospitals in the US and worldwide, and this opportunistic fungus represents an increasing threat to an ever expanding population of immune- and medically-compromised patients. Candidiasis carries unacceptably high mortality rates, about 30-60%, clearly indicating that current antifungal therapy is still ineffective, due to the limited armamentarium of antifungal agents, the toxicity displayed by some of the current therapies, and the emergence of resistance to most classes of antifungals. Moreover, there are no new effective drugs in sight, and the antifungal pipeline is mostly dry. The ability to form biofilms, microbial communities attached to surfaces, is intimately linked to the pathogenesis of C. albicans, and indeed the majority of manifestations of candidiasis are associated with biofilm formation, which further complicates treatment. As such biofilm formation represents a high value target for the development of novel antifungals. Most recently, we have carried out high content screens and identified small molecule compounds that specifically inhibit C. albicans biofilm formation. We have been developing some of these compounds as novel antifungals, having confirmed their potent biofilm-inhibitory activity, lack of toxicity and efficacy in vivo using relevant animal models of candidiasis. The main goal of the current project is to further advance the development of the current leading chemical series of compounds, for which we propose three specific objectives. i) Medicinal Chemistry. We will engage on a focused and systematic medicinal chemistry campaign to advance 3-4 structurally diverse lead chemical series in parallel, establish structure- activity relationships that improve biofilm inhibition properties while also improving physical chemical "drug-like" properties. ii) In vivo efficacy. We will test a discrete number of compounds within each chemical series in the murine model of hematogenously disseminated candidiasis, as well as in the murine models of catheter- associated candidiasis and oral candidiasis, both of which are associated with biofilm formation. iii) Insights into mechanisms of action, potential for resistance development, and further in vitro characterization. We will perform further characterization of representative compounds of each chemical series showing the most promise in animal models. These will include RNA-Sequencing and screening of mutant collections to gain insights into the molecular target(-s) and mechanism(-s) of action, serial passage assays to evaluate potential development of resistance, combination with current antifungals, as well as in vitro safety pharmacological profiling for determination of off-target activities.
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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Jose L. Lopez-Ribot其他文献
Protocol optimization for a fast, simple and economical chemical reduction synthesis of antimicrobial silver nanoparticles in non-specialized facilities
- DOI:
10.1186/s13104-019-4813-z - 发表时间:
2019-11-27 - 期刊:
- 影响因子:1.700
- 作者:
Roberto Vazquez-Muñoz;M. Josefina Arellano-Jimenez;Fernando D. Lopez;Jose L. Lopez-Ribot - 通讯作者:
Jose L. Lopez-Ribot
Fungal biofilms in human health and disease
人类健康与疾病中的真菌生物膜
- DOI:
10.1038/s41579-025-01147-0 - 发表时间:
2025-02-05 - 期刊:
- 影响因子:103.300
- 作者:
Gordon Ramage;Ryan Kean;Riina Rautemaa-Richardson;Craig Williams;Jose L. Lopez-Ribot - 通讯作者:
Jose L. Lopez-Ribot
Antifungal therapy of emCandida/em biofilms: Past, present and future
念珠菌生物膜的抗真菌治疗:过去、现在和未来
- DOI:
10.1016/j.bioflm.2023.100126 - 发表时间:
2023-12-01 - 期刊:
- 影响因子:4.900
- 作者:
Olabayo H. Ajetunmobi;Hamid Badali;Jesus A. Romo;Gordon Ramage;Jose L. Lopez-Ribot - 通讯作者:
Jose L. Lopez-Ribot
Jose L. Lopez-Ribot的其他文献
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{{ truncateString('Jose L. Lopez-Ribot', 18)}}的其他基金
High Throughput Screening of Medicines for Malaria Ventures Chemical Libraries to Identify Novel Inhibitors of Candida auris
疟疾药物的高通量筛选帮助化学库鉴定新型耳念珠菌抑制剂
- 批准号:
10383652 - 财政年份:2021
- 资助金额:
$ 36.75万 - 项目类别:
Screening a Target-Based Repurposing Library for Activity against Fungal Pathogens and Subsequent Preclinical Development of Leading Candidates
筛选基于靶点的再利用文库的抗真菌病原体活性以及主要候选药物的后续临床前开发
- 批准号:
10335279 - 财政年份:2019
- 资助金额:
$ 36.75万 - 项目类别:
Screening a Target-Based Repurposing Library for Activity against Fungal Pathogens and Subsequent Preclinical Development of Leading Candidates
筛选基于靶点的再利用文库的抗真菌病原体活性以及主要候选药物的后续临床前开发
- 批准号:
10320258 - 财政年份:2019
- 资助金额:
$ 36.75万 - 项目类别:
Screening a Target-Based Repurposing Library for Activity against Fungal Pathogens and Subsequent Preclinical Development of Leading Candidates
筛选基于靶点的再利用文库的抗真菌病原体活性以及主要候选药物的后续临床前开发
- 批准号:
10544529 - 财政年份:2019
- 资助金额:
$ 36.75万 - 项目类别:
Development of Monoclonal Antibody (Mab) Biologics against Neonatal Candidiasis
抗新生儿念珠菌病单克隆抗体 (Mab) 生物制剂的开发
- 批准号:
8425740 - 财政年份:2013
- 资助金额:
$ 36.75万 - 项目类别:
Targeting virulence against oral candidiasis in HIV/AIDS
针对艾滋病毒/艾滋病口腔念珠菌病的毒力
- 批准号:
9234520 - 财政年份:2013
- 资助金额:
$ 36.75万 - 项目类别:
Development of Monoclonal Antibody (Mab) Biologics against Neonatal Candidiasis
抗新生儿念珠菌病单克隆抗体 (Mab) 生物制剂的开发
- 批准号:
8719015 - 财政年份:2013
- 资助金额:
$ 36.75万 - 项目类别:
Targeting virulence against oral candidiasis in HIV/AIDS
针对艾滋病毒/艾滋病口腔念珠菌病的毒力
- 批准号:
8542240 - 财政年份:2013
- 资助金额:
$ 36.75万 - 项目类别:
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