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Imaging Amphotericin B's Mechanism of Action with Transient Absorption Microscopy

使用瞬态吸收显微镜成像两性霉素 B 的作用机制

基本信息

批准号：
9099045
负责人：
Tessa Rae Calhoun
金额：
$ 43.31万
依托单位：
UNIVERSITY OF TENNESSEE KNOXVILLE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9099045
关键词：
Adverse effects Amphotericin Amphotericin B Antifungal Agents Antimicrobial Resistance Automobile Driving Behavior Biological Models Candida albicans Cells Clinical Disease Drug Delivery Systems Drug effect disorder Environmental Risk Factor Ergosterol Foundations Image Investigation Ion Channel Label Life Measurement Measures Membrane Methodology Microscopy Mission Modeling Molecular Monitor Mycoses Nature Organism Pharmaceutical Preparations Polyenes Porifera Property Reporting Research Resistance Role Saccharomyces cerevisiae Series Signal Transduction Source Sterols Structure Students Surface Suspension substance Suspensions System Techniques Therapeutic Toxic effect Training and Education Translating absorption antimicrobial base chromophore design innovation instrumentation interest meetings membrane model novel strategies novel therapeutics oxidation oxidative damage prevent public health relevance quantum research study resistant strain small molecule success unilamellar vesicle

项目摘要

DESCRIPTION (provided by applicant): Project Summary The dramatic rise of antimicrobial resistance has created the need for new approaches in the design of novel drug systems. Amphotericin B (AmB) is an antifungal drug that has been used clinically for over 50 years with only limited cases of clinical resistance reported. Due to the toxic nature of AmB's side effects, alternative antifungals have been developed, but treatment with these alternatives is already generating increasing numbers of resistant strains despite a much shorter period of use. This has led to a renewed interest in the study of AmB as a better understanding of its activity could inform on how to design more effective antimicrobials with lower occurrences of resistance. A wide range of investigations has resulted in three, very different, proposed models for AmB's mechanism of action. We are proposing a series of experiments based on transient absorption microscopy which will image label-free AmB as it interacts with both living and model systems. Our hypotheses are (1) that our proposed methodology will be able to distinguish between the different proposed models of AmB activity and (2) that the mechanism of action by which AmB interacts with a membrane exists as an environmentally driven interplay between the proposed models of ergosterol sequestration, ion channel formation, and oxidative damage. In the first specific aim of this project we will monitor the distribution and orientation of AmB in giant unilamellar vesicles and S. cerevisiae and C. albicans cells. The second specific aim will elucidate the role of aggregation in the mechanism of AmB's interaction. This aggregation is dependent on the environmental conditions making it a likely driver for which model of action AmB employs while also having important implications for the delivery of the drug. Overall, these innovative studies fit well within NIGMS's mission to "lay the foundation for advancements in disease treatment" and will provide hands-on training and education with cutting-edge imaging instrumentation for four students, including those at both the undergraduate and graduate levels.