Interspecies reservoirs of antibiotic resistance for Neisseria gonorrhoeae

淋病奈瑟菌抗生素耐药性的种间储存库

• 批准号: 10705474
• 负责人: Crista Burke Wadsworth
• 金额: $ 44.39万
• 依托单位: ROCHESTER INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705474
• 关键词: Admixture; Alleles; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Azithromycin; Biology; Ceftriaxone; Clinical; Collection; Combined Antibiotics; Coupled; DNA; Development; Effectiveness; Etiology; Evolution; Experimental Genetics; Future; Genetic Recombination; Genome; Genomic Segment; Genomics; Genotype; Goals; Horizontal Gene Transfer; Knowledge; Laboratory Research; Maps; Mediating; Methods; Mutation; Neisseria; Neisseria elongata; Neisseria gonorrhoeae; Neisseria lactamica; Neisseria meningitidis; Pathogenicity; Patients; Pharmaceutical Preparations; Phenotype; Phylogenetic Analysis; Population; Positioning Attribute; Predisposition; Prevalence; Public Health; Publishing; Resistance; Risk; Scanning; Source; Students; Surveillance Methods; Surveys; Testing; Training and Education; Trees; Work; azithromycin resistance; bioinformatics pipeline; candidate validation; clinically relevant; comparative genomics; experimental study; falls; flexibility; genetic variant; genome sequencing; genomic locus; graduate student; homologous recombination; improved; infection rate; member; novel; pathogen; permissiveness; prevent outbreaks; resistance allele; resistance gene; resistance mechanism; resistance mutation; resistant strain; training opportunity; undergraduate student; uptake; whole genome

PROJECT SUMMARY Antibiotic resistance in Neisseria gonorrhoeae is an urgent threat to public health, with the emergence of strains resistant to current clinically-approved antibiotics, and infection rates simultaneously rising (up 92% since 2009). Substantial effort has been spent on identifying resistance mechanisms to antibiotic therapies currently circulating within the gonococcal population. However, these surveys often overlook a known source of resistance for gonococci – the commensal Neisseria. Neisseria promiscuously share DNA with one another, which has been demonstrated to facilitate rapid adaptation and evolutionary change. For example, the majority of reduced susceptibility to both azithromycin and ceftriaxone in N. gonorrhoeae populations has been acquired though horizontal transfer and subsequent spread of commensal alleles. As resistance has been shown to be directly selected for in commensals after antibiotic usage in patients, these species will always be a persistent threat for resistance donation to N. gonorrhoeae. Thus, the overall goal of this project is to profile the Neisseria resistome, or the total collection of antibiotic resistance mechanisms available to members within the genus. The knowledge gained from this proposal may directly support the development of improved surveillance methods that may aid future resistance outbreak prevention as a result of DNA donation. In Aim 1, we will use experimental evolution of 10 commensal isolates to 6 antibiotics to nominate novel mechanisms of resistance that may be available to pathogenic members of the genus. This aim builds on our published work demonstrating the feasibility of rapid resistance evolution (< 20 days) in commensals, and the ease of identifying the underlying casual mutations via whole genome sequencing. In Aim 2, we will use population genomics to determine the genomic regions that demonstrate evidence of horizontal transfer from commensals to gonococci. This aim will also provide evidence supporting the possibility of novel derived mutations uncovered in Aim 1 and those that have previously been described, in being maintained in natural populations. In Aim 3, we will validate novel resistance mechanisms and assess their likelihood of transfer to N. gonorrhoeae. Transformations of candidate resistance mutations into ancestral commensal strains (not evolved) and a piliated N. gonorrhoeae will together 1) prove causality of novel mutations, and 2) provide experimental evidence of the likelihood of transfer into a Neisseria pathogen. The PI has demonstrated that these experiments are feasible at the undergraduate and graduate student levels, in both the research laboratory and in the classroom, and will provide exceptional educational and training opportunities for RIT students.

项目摘要 Neiserseria Gonorrhoeae的抗生素耐药性是对公共卫生的紧迫威胁，随着出现 对当前临床批准的抗生素抗性菌株的抗菌菌株，感染率类似上升（上升） 自2009年以来为92％）。已经花费了大量精力来识别抗生素的抗性机制 目前正在淋球菌种群中循环的疗法。但是，这些调查常常忽略 淋球菌 - 共生奈瑟氏菌的已知抗药性来源。 Neisseria有望分享 DNA彼此，已被证明可以促进快速适应和进化 改变。例如，大多数降低了对N. azithromycin和头孢曲松的敏感性。 通过水平转移和随后的传播，已经获得了淋病种群 共生等位基因。由于已显示电阻已直接在Comensals中直接选择 患者的抗生素使用情况，这些物种将永远是抵抗捐赠的持续威胁 N. Gonorrhoeae。这是该项目的总体目标是介绍Neisereria resinome，或者总计 该属内成员可用的抗生素耐药机制的收集。知识 从该提案中获得的可以直接支持改进的监视方法的发展 由于DNA捐赠，可能有助于预防未来的抵抗暴发。在AIM 1中，我们将使用 10种共生分离株与6种抗生素的实验进化，以提名新的机制 属的病原体可能可用的抗性。这个目标建立在我们已发表的 表明在共生中快速阻力演化（<20天）的可行性以及轻松的工作 通过整个基因组测序来识别潜在的休闲突变。在AIM 2中，我们将使用 人群基因组学确定证明水平转移证据的基因组区域 从共生到淋球菌。这个目标还将提供支持新颖可能性的证据 在AIM 1中发现的派生突变以及先前描述的突变， 维持在自然种群中。在AIM 3中，我们将验证新颖的阻力机制和评估 他们转移到淋病的n。。候选抗性突变转变为 祖先的共生菌株（未进化），堆积的淋病。 新型突变，以及2）提供了转移到奈瑟氏菌的可能性的实验证据 病原。 PI证明，这些实验在本科生和 研究生级别的研究实验室和课堂上都将提供 RIT学生的出色教育和培训机会。