Macrolide resistance transfer in Streptococcus pyogenes

化脓性链球菌中的大环内酯类耐药性转移

• 批准号: 10474268
• 负责人: Debra E BESSEN
• 金额: $ 20.31万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-24 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10474268
• 关键词: Abbreviations; Address; Adult; Affect; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Antibiotic Resistance; Biological; Biological Assay; Biology; Cells; Cessation of life; Child; Chloramphenicol; Clindamycin; Clinical; Colony-forming units; Consumption; Data; Disease; Disease model; Drug resistance; Elements; Environment; Epidemiology; Epithelial; Erythromycin; Event; Exotoxins; Experimental Models; Foundations; Future; Gene Proteins; Genes; Genetic; Genetic Structures; Goals; Health; High Prevalence; Horizontal Gene Transfer; Human; Hypersensitivity; In Vitro; Incidence; Infection; Kanamycin; Knowledge; Lateral; Link; Macrolide-resistance; Macrolides; Methyltransferase; Mobile Genetic Elements; Modification; Molecular; Molecular Probes; Morbidity - disease rate; Necrotizing fasciitis; Nucleotides; Oropharyngeal; Partner in relationship; Pathology; Patients; Penicillin Allergy; Penicillin-Binding Proteins; Pharyngeal structure; Phenotype; Population Analysis; Process; Production; Protocols documentation; Quantitative Reverse Transcriptase PCR; Recombinants; Reporting; Resistance; Ribosomal RNA; Skin; Spectinomycin; Streptococcal Infections; Streptococcus pyogenes; Streptomycin; Structure; Surface; Testing; Tetanus Helper Peptide; Tetracyclines; Time; Toxic Shock Syndrome; Toxin; Vaccines; Virulence; Virulence Factors; Work; antitoxin; beta-Lactam Resistance; beta-Lactams; design; epidemiologic data; fitness; genetic analysis; genetic architecture; human pathogen; improved; intraperitoneal; lincosamide; mortality; mouse model; next generation sequencing; pathogen; pathogenic bacteria; population survey; resistance gene; resistant strain; tool; tool development; transcriptome; user-friendly; vaccine access; vaccine development; vpr Genes; web site; whole genome

PROJECT SUMMARY Group A Streptococcus (GAS) is a strict human pathogen that primarily infects the epithelia at the throat or skin, leading to ~750 million infections per year. High rates of morbidity and mortality result from invasive GAS (iGAS) disease. Despite its importance as a global pathogen, there is no vaccine available for GAS. In the C.D.C.'s Antibiotic Resistance Threats Report of 2019, erythromycin-resistant GAS are listed as a “concerning threat” and the % of invasive GAS (iGAS) isolates resistant to erythromycin has recently tripled. Macrolides are commonly prescribed for patients with β-lactam allergies, and lincosamides are highly effective against iGAS disease because exotoxin production is halted. The problem of antibiotic-resistance in GAS is further compounded by 2019-2020 reports on the emergence of stable β-lactam resistance due to altered penicillin- binding proteins; the potential for lateral spread of resistance genes to other GAS strains is very high. The proposed study seeks a deeper understanding of the biological causes and clinical consequences of the acquisition by GAS of mobile genetic elements (MGEs) harboring macrolide-resistance genes (R-genes). Aim 1 seeks to define the genetic architecture of the (near) complete repertoire of MGEs that harbor macrolide- resistance genes in GAS. Aim 2 uses experimental models of horizontal transfer of R-gene-MGEs between GAS strains, to optimize microenvironmental conditions and to generate isogenic pairs of parental-recipient and new recombinant strains. Aim 3 evaluates the effect of MGE acquisition on host cell phenotypes that are independent of drug-resistance; several cargo genes are predicted to alter global gene expression and/or contribute to virulence. Transcriptomes and fitness will be compared for the isogenic pairs. A mouse model for iGAS disease will test the hypothesis that MGE acquisition leads to an increase in the intrinsic virulence of the new recombinant. If correct, data may explain the epidemiological findings on the high association of macrolide-resistance with iGAS disease and thereby, provide a platform for future studies that probe molecular mechanisms. Tools to be developed from the proposed work include a consolidated structural organization for the macrolide- resistance MGEs, to be posted on the interactive user-friendly www.pubmlst.org website (Aim 1), and improved experimental protocols for horizontal gene transfer by filter-mating (Aim 2). In addition to testing the hypothesis that MGEs impart phenotypic changes in an antibiotic-free environment, transcriptome analysis (Aim 3) is exploratory and may provide a window into critical molecular mechanisms.

项目概要 A 组链球菌 (GAS) 是一种严格的人类病原体，主要感染咽喉或呼吸道的上皮细胞。 侵入性 GAS 每年导致约 7.5 亿人感染。 (iGAS) 疾病作为一种全球病原体很重要，但目前还没有针对 GAS 的疫苗。 CDC 2019 年抗生素耐药性威胁报告中，红霉素耐药性 GAS 被列为“值得关注的威胁” 威胁”，并且对红霉素耐药的侵入性 GAS (i​​GAS) 菌株的百分比最近增加了两倍。 通常用于 β-内酰胺过敏患者，林可酰胺类药物对 iGAS 非常有效 由于外毒素产生停止，GAS 中的抗生素耐药性问题更加严重。 2019-2020 年关于由于青霉素改变而出现稳定的 β-内酰胺耐药性的报告使情况更加复杂。 结合蛋白；抗性基因向其他 GAS 菌株横向传播的可能性非常高。 拟议的研究旨在更深入地了解该疾病的生物学原因和临床后果 通过 GAS 获取含有大环内酯类抗性基因（R-基因）的移动遗传元件（MGE）。 1 试图定义含有大环内酯的（近）完整 MGE 的遗传结构 GAS 中的抗性基因使用 R 基因-MGE 之间水平转移的实验模型。 GAS菌株，优化微环境条件并产生亲本-受体的同基因对 目标 3 评估了 MGE 获取对宿主细胞表型的影响。 与耐药性无关；预计多个货物基因会改变全局基因表达和/或 将比较同基因对小鼠模型的转录组和适应性。 iGAS 疾病将检验这样的假设：MGE 的获得会导致 MGE 的内在毒力增加。 如果正确的话，数据可以解释流行病学发现的高度相关性。 iGAS 疾病对大环内酯类药物的耐药性，从而为未来探索分子机制的研究提供了一个平台。 机制。 从拟议的工作中开发的工具包括大环内酯类的统一结构组织 阻力 MGE，将发布在交互式用户友好型 www.pubmlst.org 网站上（目标 1），并改进 通过过滤交配进行水平基因转移的实验方案（目标 2）。 MGE 在无抗生素环境中赋予表型变化，转录组分析（目标 3）是 探索性的，可能提供了解关键分子机制的窗口。