Exploration of the oropharyngeal resistome as a reservoir of antimicrobial resistance in Neisseria gonorrhoeae

口咽耐药组作为淋病奈瑟氏菌耐药性库的探索

• 批准号: 10657789
• 负责人: Olusegun Olasunkanmi Soge
• 金额: $ 19.02万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10657789
• 关键词: 16S ribosomal RNA sequencing; Address; Anatomy; Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Antimicrobial susceptibility; Bacteria; Bioinformatics; COVID-19 pandemic; Case Study; Ceftriaxone; Cephalosporin Resistance; Cephalosporins; Clinic; Clinical; Coculture Techniques; County; Cross-Sectional Studies; Data; Development; Diagnosis; Drug-resistant Neisseria Gonorrhoeae; Enrollment; Environment; Epidemic; Event; Evolution; Exposure to; Fluoroquinolones; Frequencies; Generations; Genes; Genetic; Genetic Determinism; Genetic Markers; Goals; Gonorrhea; Guidelines; HIV; Health Priorities; Human; Humanities; In Vitro; Incidence; Infection; Knowledge; Laboratories; MALDI-TOF Mass Spectrometry; Macrolides; Metagenomics; Methods; Minimum Inhibitory Concentration measurement; Multi-Drug Resistance; Mutation; Neisseria; Neisseria gonorrhoeae; Oropharyngeal; Patients; Penicillins; Pharmaceutical Preparations; Phenotype; Play; Population; Predisposition; Prevalence; Prevention; Public Health; Quality Control; Recommendation; Reporting; Resistance; Resistance development; Resistance profile; Risk; Role; Sampling; Sexual Health; Sexually Transmitted Diseases; Specimen; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; System; Testing; Tetracyclines; Therapeutic; Time; Treatment Protocols; Woman; Work; antimicrobial; commensal bacteria; effective therapy; emerging antimicrobial resistance; global health; high risk; improved; insight; men; men who have sex with men; metagenomic sequencing; microbial; microbiota; next generation sequencing; novel; pharyngeal gonorrhea; recruit; resistance gene; resistance mechanism; resistance mutation; sex

Project Summary/Abstract Gonorrhea is one of the most common sexually transmitted infections (STIs) globally, and prior to the COVID- 19 pandemic, the second most common reportable infection in the U.S. In the past decade, there have been significant increases in gonorrhea among men who have sex with men (MSM) in the US, with a 375% increase observed from 2010–2018. At the same time, the percentages of antimicrobial-resistant Neisseria gonorrhoeae (AMR-NG) continues to increase markedly in MSM. Despite the significant increase in the prevalence of AMR- NG, the drivers and reservoirs of AMR-NG especially for oropharyngeal gonorrhea commonly diagnosed in MSM and responsible for all the reported cases of failed ceftriaxone treatment are yet to be fully elucidated. The oropharynx is reservoir for AMR-NG because it harbors a large microbiota and repertoire of AMR genes. The overall goal of this proposal is to describe comprehensively the oropharyngeal resistome of men who are a priority population for STI and HIV control and prevention. In Aim 1, we will use culturomics to identify NG and commensal bacteria, determine their AMR profiles, and use the phenotypic AMR data for stringent quality control of our oropharyngeal resistome profiling (Aim 2). In Aim 2, we will use an unbiased culture-independent metagenomic sequencing and comprehensive bioinformatic analysis to determine the oropharyngeal resistome of MSM and MSW. In Aim 3, we will sequence 150 commensal Neisseria spp. paired with NG isolates obtained from the same patient when isolated (Aim 1) to demonstrate that they share the same genetic markers of AMR. We will define the genetic mechanisms of AMR among multidrug-resistant (MDR) commensal Neisseria spp., and investigate the relative frequency of in vitro transfer of AMR from 10 different species of commensal Neisseria to fully susceptible and genetically diverse recipient strains of NG. We expect that the results from these studies will provide urgently needed data on the repertoire of AMR genes and genetic determinants facilitating the evolution of NG resistance to antibiotics recommended for gonorrhea treatment including ceftriaxone, the last remaining highly effective treatment option for gonorrhea, and paving the way for improved proactive identification and mitigation of emerging AMR threats. Our data will immediately contribute to the surveillance of AMR threats in MSM disproportionately impacted by gonorrhea and HIV epidemics, and guide efforts to develop novel antimicrobials for combatting MDR-NG. Public Health Significance. This study will define the magnitude and diversity AMR in the human oropharynx, an anatomic site thought to play a central role in the emergence of AMR-NG, and will provide new insights into which bacteria and under what circumstances NG may acquire AMR. This knowledge will provide important insights into how AMR-NG develops, critically important information in developing strategies to contain the threat of AMR-NG and for development of novel antimicrobials.

项目概要/摘要 淋病是全球最常见的性传播感染 (STI) 之一，在新冠疫情之前 19大流行病是美国第二大最常见的可报告感染。在过去十年中， 美国男男性行为者 (MSM) 的淋病显着增加，增加了 375% 同时观察到 2010 年至 2018 年耐药淋病奈瑟菌的百分比。 尽管 AMR-NG 的患病率显着增加，但 MSM 中的 AMR-NG 继续显着增加。 NG，AMR-NG 的驱动因素和储存库，特别是 MSM 中常见的口咽淋病 以及所有报告的头孢曲松治疗失败病例的责任尚未完全阐明。 口咽部是 AMR-NG 的储存库，因为它含有大量的微生物群和 AMR 基因库。 该提案的总体目标是全面描述男性的口咽抵抗组。 性传播感染和艾滋病毒控制和预防的重点人群 在目标 1 中，我们将使用培养组学来识别 NG 和 共生细菌，确定其 AMR 谱，并使用表型 AMR 数据进行严格的质量控制 我们的口咽抵抗组分析（目标 2）在目标 2 中，我们将使用独立于文化的无偏见的方法。 宏基因组测序和综合生物信息分析以确定口咽耐药组 在目标 3 中，我们将对与获得的 NG 分离株配对的 150 个共生奈瑟菌进行测序。 分离时来自同一患者（目标 1），以证明他们具有相同的 AMR 遗传标记。 我们将定义多重耐药 (MDR) 共生奈瑟菌属中 AMR 的遗传机制， 并研究了来自 10 种不同共生物种的 AMR 体外转移的相对频率 奈瑟氏球菌对 NG 完全敏感且具有遗传多样性的受体菌株，我们期望得到这样的结果。 这些研究将提供有关 AMR 基因和遗传决定因素的急需数据 促进 NG 对推荐用于淋病治疗的抗生素耐药性的进化，包括 头孢曲松是淋病最后一种高效治疗选择，为改善淋病铺平了道路 我们的数据将立即有助于主动识别和缓解新出现的 AMR 威胁。 监测受淋病和艾滋病毒流行影响不成比例的 MSM 中的 AMR 威胁，并提供指导 开发新型抗菌药物来对抗 MDR-NG。 公共卫生意义 这项研究将确定人类口咽部 AMR 的程度和多样性， 一个被认为在 AMR-NG 的出现中发挥核心作用的解剖部位，并将提供新的见解 哪些细菌以及在什么情况下 NG 可能获得 AMR，这些知识将提供重要的帮助。 了解 AMR-NG 如何发展，对于制定遏制威胁的战略至关重要的信息 AMR-NG 和新型抗菌药物的开发。