Interferometry to understand beta-lactam heteroresistance

干涉测量法了解 β-内酰胺异质抗性

• 批准号: 10798548
• 负责人: Peter Yunker
• 金额: $ 12.65万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10798548
• 关键词: Address; Adopted; Agreement; Antibiotic Resistance; Antibiotic susceptibility; Antibiotics; Award; Bacteria; Biomedical Research; Biophysics; Cells; Clinical Microbiology; Diagnostic; Dyes; Equipment; Funding; Growth; Hour; Instruction; Interferometry; Intermediate resistance; Laboratories; Manuals; Measurement; Measures; Medical; Minor; Modern Medicine; Parents; Phenotype; Physics; Population; Predisposition; Process; Property; Research; Resistance; Stains; Testing; Therapeutic; Time; Treatment Failure; Work; World Health Organization; beta-Lactam Resistance; beta-Lactams; biophysical analysis; clinically relevant; design; experimental study; flexibility; materials science; new technology; parent grant; ultra high resolution

The World Health Organization (WHO) has highlighted antibiotic resistance as one of the greatest medical challenges of the 21st century. Choosing effective antibiotics is therefore critical, and basing antibiotic selection on bacterial susceptibilities potentially offers the greatest therapeutic benefit. Current antibiotic susceptibility tests are unable to detect a common form of resistance (present in more than 25% of antibiotic-bacteria combinations) known as heteroresistance, in which a minor subpopulation of bacterial cells is phenotypically resistant. These resistant cells rapidly expand in the presence of an antibiotic and thus can cause treatment failure. Developing a new susceptibility test is further complicated by the requirements of the clinical microbiology laboratory; to be adopted, a susceptibility test must require minimal manual labor, work robustly, and be inexpensive – properties that are often at odds with high sensitivity. Based on these issues, there is broad agreement that a new technological approach is required. In the parent grant, we proposed to develop a new susceptibility test using interferometry to measure bacterial population topography. The use of interferometry to measure topography has no precedence in antibiotic susceptibility testing, and little precedence in biomedical research in general. However, it is common in physics and materials science as it is rapid, doesn’t require dyes or stains, and provides super-resolution measurements of topography. Interferometers are inexpensive and robust. In exciting preliminary results, we have demonstrated that with interferometry we can detect heteroresistance in 2 hours, and even distinguish low levels of heteroresistance from susceptibility. In this equipment supplement, we are requesting funds to purchase another interferometer. In the process of developing an interferometry-based susceptibility test, we made a discovery about the biophysics of beta-lactam heteroresistance. In line with the parent grant’s proposed work on measuring and understanding bacterial topography, as well as proposed work on interferometry-based diagnostics, here we propose to investigate how the growth of beta-lactam resistant cells depends on the local concentration of resistant cells. These experiments are necessarily long (each takes at least 24 hours) and drawing conclusions will require testing many different strains against different beta-lactams, and thus require additional equipment. This project addresses fundamental questions about the biophysics of rare resistant cells. Further, as beta- lactams are the most used class of antibiotics, the results of the work proposed here will also hold clinical relevance.

世界卫生组织（WHO）强调抗生素耐药性是最大的医学问题之一