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The Role of Enterococcus Unique Hypothetical EF1909 in Intrinsic β-lactam Resistance

肠球菌独特的假设 EF1909 在内在 β-内酰胺耐药性中的作用

基本信息

批准号：
10464409
负责人：
Michael S Gilmore
金额：
$ 25.3万
依托单位：
MASSACHUSETTS EYE AND EAR INFIRMARY
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：
2022-02-08 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10464409
关键词：
Affect Ampicillin Anabolism Animal Model Animals Antibiotic Resistance Antibiotics Back Biocide Ceftriaxone Cell Wall Cell physiology Cell surface Cells Chemicals Complement Data Desiccation ESKAPE pathogens Enterococcus Enterococcus faecalis Enterococcus faecium Enzymes Explosion Exposure to Genes Genetic Transcription Genome Goals Growth Habitats Hospitals Human Infection Investigation Medicine Microbe Monobactams Multi-Drug Resistance Nosocomial Infections PAWR protein Pathway interactions Penicillins Peptidoglycan Phenotype Play Proteins Research Resistance Reverse Transcriptase Polymerase Chain Reaction Role Side Starvation Structural Models Testing Time Work acronyms antimicrobial resistant infection beta-Lactam Resistance beta-Lactams biological adaptation to stress cellular engineering global health gut microbiome inhibitor member mutant novel pathogen premature resistant strain screening trait transcriptome sequencing transposon sequencing

项目摘要

Project summary: Enterococci are leading causes of multidrug resistant hospital acquired infection – the first E in the ESKAPE acronym. We recently showed that the genus Enterococcus differs from its closest extant ancestors in having evolved enhanced traits for survival, including to starvation and desiccation, as well as to challenge by antibiotics and other biocides that target the cell surface. That is, in diverging from its ancestors hundreds of millions of years ago, it gained features making the cell more rugged and impermeable. We found that enterococci possess 10 genes that are rare or do not exist outside of the genus. Moreover, we found that one of these, encoding a hypothetical protein, contributes to intrinsic resistance to b-lactams – the largest class of antibiotics used in human medicine. As a result of this intrinsic resistance, this antibiotic class has been of limited use in controlling enterococcal infection. Here we propose to validate the preliminary results implicating this gene, termed EF1909, in contributing to intrinsic b-lactam resistance and more rigorously and fully assess the phenotype of cells engineered to lack this feature. We additionally assess when in the growth cycle that EF1909 is expressed and determine whether its presence/absence results in cell wall peptiglycan of altered composition as implicated by its contribution to intrinsic b-lactam resistance. If we are able to substantiate the preliminary indications of phenotype in this exploratory work, this would raise the prospect of then screening for EF1909 inhibitors that would be predicted to render enterococci now vulnerable to inexpensive and readily available b-lactam antibiotics. Rendering enterococci readily treatable by b-lactams would be an advance of very high impact for global health.

项目总结: