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.

项目摘要 A组链球菌（气）是严格的人类病原体，主要感染喉部或 皮肤，每年大约7.5亿感染。侵入性气体的发病率和死亡率高。 （IGAS）疾病。尽管它是全球病原体的重要性，但仍没有疫苗可用于天然气。在 C.D.C. 2019年的抗生素抗性威胁报告，耐红霉素的气体被列为“有关的 威胁”和侵入性气体（IGA）分离株的百分比最近抗红霉素。 通常针对患有β-内酰胺过敏的患者处方 疾病是因为产生外毒素。气体中抗生素耐药性的问题进一步 根据2019 - 2020年的报道，关于稳定的β-内酰胺耐药性因青霉素改变而产生的报告。 结合蛋白；电阻基因向其他气体菌株横向扩散的潜力非常高。 拟议的研究寻求对生物学原因和临床后果的更深入了解 通过气体的移动遗传因素（MGE）获取，该元素（MGES）具有抗大环内酯类化基因（R-Genes）。目的 1试图定义（近）完全库的MACROLIDE- 气体中的抗性基因。 AIM 2使用R-GENE-MGES水平转移的实验模型 气体菌株，优化微环境条件并产生父母居民的等源性对 和新的重组菌株。 AIM 3评估MGE获取对宿主细胞表型的影响 独立于抗药性；预计几种货物基因会改变全局基因表达和/或 有助于病毒。对于等源性对，将比较转录组和适应性。鼠标模型 IGAS病将检验以下假设：MGE获取会导致固有病毒的增加 新的重组。如果正确，数据可能会解释有关高关联的流行病学发现 大花环抗IGAS疾病，从而为将来的研究提供了一个平台，以探测分子 机制。 从拟议的工作中开发的工具包括用于大环内酯类的合并结构组织 电阻MGE，将发布在交互式用户友好www.pubmlst.org网站上（AIM 1），并改进了 通过滤波器交配的水平基因转移的实验方案（AIM 2）。除了检验假设 MGE在无抗生素环境中散发了表型变化，转录组分析（AIM 3）是 探索性，可以提供关键分子机制的窗口。