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.

项目概要： 肠球菌是多重耐药性医院获得性感染的主要原因——第一个 E ESKAPE 缩写。我们最近表明肠球菌属与其最接近的属不同 现存的祖先进化出了增强的生存特征，包括饥饿和 干燥，以及抗生素和其他针对细胞表面的杀菌剂的挑战。 也就是说，在与数亿年前的祖先不同的过程中，它获得了使 电池更加坚固且不渗透。我们发现肠球菌拥有 10 个基因， 稀有或不存在于该属之外。此外，我们发现其中之一，编码 假设的蛋白质，有助于对 b-内酰胺（最大的一类）具有内在抵抗力 用于人类医学的抗生素。由于这种内在的耐药性，该类抗生素具有 在控制肠球菌感染方面的用途有限。在这里我们建议验证 初步结果表明该基因（称为 EF1909）有助于产生内在的 β-内酰胺 耐药性，并更严格、更全面地评估被设计为缺乏这种耐药性的细胞的表型 特征。我们还评估了 EF1909 在生长周期中何时表达并确定 它的存在/不存在是否会导致细胞壁肽聚糖的组成发生改变 通过其对内在β-内酰胺耐药性的贡献。如果我们能够证实初步的结论 这项探索性工作中的表型迹象，这将提高随后筛选的前景 EF1909 抑制剂预计会使肠球菌现在容易受到廉价的影响 和现成的β-内酰胺抗生素。使肠球菌易于被 β-内酰胺治疗 这将是对全球健康产生巨大影响的一项进步。