权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Overcoming Emerging Aspergillus fumigatus Azole Resistance Via Protease Inhibition

通过蛋白酶抑制克服新出现的烟曲霉唑抗性

基本信息

批准号：
10547781
负责人：
Robert Andrew Cramer
金额：
$ 44.62万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10547781
关键词：
Address Animal Model Antifungal Agents Aspergillosis Aspergillus fumigatus Azole resistance Azoles Biological Assay Cells Chemicals Chemistry Clinical Complex Data Disease Disease Progression Drug Kinetics Drug resistance Environment Fostering Fungal Drug Resistance Genetic Genomics Goals Growth Human Hypoxia Impairment In Vitro Infection Laboratories Lead Libraries Ligase Link Measures Modeling Molds Molecular Target Morbidity - disease rate Mus Mycoses Organism Outcome Oxygen Pathway interactions Peptide Hydrolases Pharmaceutical Preparations Pharmacology Pharmacotherapy Phase Phenotype Physiological Predisposition Property Reporter Resistance Series Serine Protease Signal Pathway Site Specificity Therapeutic Toxic effect Toxicology Transcriptional Activation Treatment outcome Validation Virulence acute toxicity analog candidate identification cytotoxicity druggable target fitness fungus improved in vitro Assay in vivo in vivo evaluation inhibitor mortality mouse model mutant novel pathogenic fungus pharmacologic pre-clinical resistant strain response scaffold small molecule small molecule libraries synergism therapeutic candidate ubiquitin-protein ligase

项目摘要

PROJECT SUMMARY. Infections caused by the filamentous fungus Aspergillus fumigatus and related species are associated with significant morbidity and mortality despite contemporary antifungal drug therapies. Many factors contribute to poor treatment outcomes including the physiological state of the fungus at the site of infection and the global emergence of triazole drug resistant strains. One major regulatory mechanism used by the fungus to progress disease and resist triazole drug activity is proteolytic activation of the transcriptional regulator, SrbA. Activation of SrbA in vivo is absolutely required for fungal virulence and intrinsic triazole drug resistance, as null mutants of SrbA regulatory factors such as the fungal specific activating serine protease RbdB and E3 ubiquitin ligases (DSCs) are avirulent in animal models of invasive aspergillosis (IA) and have significant increases in triazole susceptibility. The objective of this proposal in response to RFA-AI-17-036 is to identify small molecules that inhibit SrbA activation and develop them into advanced therapeutic candidates with broad-spectrum activity against triazole resistant filamentous fungi. Potent inhibitors of the SrbA- dependent signaling pathway will be developed for clinical use as an adjunctive therapy in combination with a triazole antifungal agent that is used to treat IA. The adjunctive therapy is expected to provide several advantages over triazole monotherapy, including growth inhibition in hypoxic conditions and increased antifungal activity of the triazole drug in both drug susceptible and drug resistant infections. As the SrbA pathway is conserved among most human fungal pathogens, some of which are inherently azole resistant, we anticipate broad spectrum clinical utility beyond infections caused by A. fumigatus. Our approach leverages the availability of well characterized protease and ligase inhibitor chemical libraries, both known druggable targets in many disease settings, with the expertise of Microbiotix Inc. and the Cramer Laboratory at Dartmouth. The R21 phase of this application will utilize high-throughput cell based screens of defined targeted small molecule libraries to identify and confirm SrbA regulatory protease and/or ligase inhibitors and validate their antifungal activity, pathway specificity, and mammalian toxicity of early hits and leads. In the R33 phase, validated hits will be chemically optimized, validated, defined pharmacologically, determine mechanism of action, and finally proceed to in vivo pharmacologic and toxicology profiling and antifungal efficacy in established murine models of invasive aspergillosis.

项目总结。由丝状真菌烟曲霉及其相关种引起的感染