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

• 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
• 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

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： 肠球菌是耐多药医院获得性感染的主要原因-第一个E ESKAPE的首字母缩写。我们最近发现，肠球菌属与其最接近的 现存的祖先进化出了增强的生存特征，包括饥饿和 干燥，以及以细胞表面为目标的抗生素和其他杀生剂的挑战。 也就是说，在与数亿年前的祖先背道而驰时，它获得了使 牢房更加坚固耐用，不透气。我们发现肠球菌有10个基因，它们是 稀有的或不存在于属外的。此外，我们发现其中之一，编码一个 假设的蛋白质，有助于对β-内酰胺类抗生素的内在耐药-最大的一类 人类医学中使用的抗生素。由于这种内在的耐药性，这种抗生素类别具有 在控制肠球菌感染方面的作用有限。在这里，我们建议验证 初步结果表明，这种名为EF1909的基因与固有的β-内酰胺有关 并更严格和全面地评估缺乏这种抗性的细胞的表型 特写。我们还评估了EF1909在生长周期中的表达时间，并确定了 它的存在/不存在是否会导致细胞壁多糖组分改变 通过它对β-内酰胺类固有耐药的贡献。如果我们能证实初步的 在这项探索性工作中的表型适应症，这将提高随后筛选的前景 对于EF1909抑制剂来说，这将使肠球菌现在容易受到廉价药物的影响 以及随手可得的β-内酰胺类抗生素。使肠球菌易于用β-内酰胺类药物治疗 这将是一个对全球健康产生非常大影响的进步。