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

基本信息

项目摘要

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 淋病奈瑟菌的抗生素耐药性是对公共卫生的紧迫威胁, 对目前临床批准的抗生素耐药的菌株,感染率同时上升(上升 2009年以来的92%)。在确定抗生素的耐药性机制方面已经花费了大量的努力 目前在淋球菌群体中流行的治疗方法。然而,这些调查往往忽视了 一种已知的淋球菌耐药性来源-奈瑟菌混杂地分享 DNA相互作用,这已被证明有助于快速适应和进化 变化例如,大多数对阿奇霉素和头孢曲松敏感性降低的N。 淋病种群通过水平转移和随后的传播获得, 等位基因。由于阻力已被证明是直接选择的, 抗生素的使用,这些物种将永远是一个持久的威胁,耐药捐赠, N.淋病因此,本项目的总体目标是分析奈瑟菌耐药基因组,或总耐药基因组。 该属内成员可用的抗生素耐药性机制的集合。知识 从这一建议中获得的信息可能直接支持改进监测方法的发展, 可能有助于未来的耐药性爆发预防作为DNA捐赠的结果。在目标1中,我们将使用 10种抗生素的实验进化,以命名新的机制, 该属的致病成员可能具有的抗性。这一目标建立在我们公布的 工作证明了快速抗性进化的可行性(< 20天),以及 通过全基因组测序来识别潜在的偶然突变。在目标2中,我们将使用 群体基因组学,以确定显示水平转移证据的基因组区域 从细菌到淋球菌这一目标也将提供证据支持小说的可能性 Aim 1中发现的衍生突变和先前描述的那些, 在自然人群中。在目标3中,我们将验证新的耐药机制并评估 转移到N的可能性。淋病候选耐药突变转化为 祖先共生菌株(未进化)和有毛N.淋病将一起1)证明因果关系 新的突变,和2)提供转移到奈瑟菌的可能性的实验证据 病原体PI已经证明,这些实验在本科生中是可行的, 研究生水平,在研究实验室和课堂上,并将提供 为RIT学生提供特殊的教育和培训机会。

项目成果

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