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.

项目摘要/摘要 淋病是全球最常见的性传播感染（性传播感染）之一 19大流行是过去十年美国第二常见的报告感染 在美国与男性发生性关系（MSM）的男性中的淋病显着增加，增加了375％ 观察到2010年至2018年。同时，抗菌耐药的淋病的百分比 （AMR-NG）在MSM中继续显着增加。尽管AMR的患病率显着提高 NG，AMR-NG的驱动因素和储层，尤其是针对MSM中通常诊断出的口咽淋病 负责所有报告的头孢曲松治疗失败的病例尚未完全阐明。这 口咽是AMR-NG的储层，因为它具有大型的微生物群和AMR基因的曲目。这 该提案的总体目标是全面描述口咽的男性，这些人是一个 STI和HIV控制与预防的优先人群。在AIM 1中，我们将使用文化来识别NG和 共生细菌，确定其AMR轮廓，并使用表型AMR数据进行严格的质量控制 我们的口咽抗性分析（AIM 2）。在AIM 2中，我们将使用公正的文化独立 元基因组测序和全面的生物信息学分析，以确定口咽restome MSM和MSW。在AIM 3中，我们将对150个共生奈瑟氏菌属于序列。与获得的NG分离株配对 分离时从同一患者那里（目标1），以证明他们具有相同的AMR遗传标记。 我们将定义抗多药（MDR）Censensal neisseria spp。中AMR的遗传机制。 并研究从10种不同种类的共生体体外转移的相对频率 奈瑟氏菌对NG的完全易感和一般多样化的受体菌株。我们期望来自 这些研究将提供有关AMR基因和遗传确定剂库的急需数据 促进NG对抗生素的耐药性的进化，推荐用于淋病治疗 头孢曲松，这是淋病的最后剩下的高效治疗选择，并为改进的道路铺平了道路 主动识别和缓解新兴AMR威胁。我们的数据将立即有助于 MSM中AMR威胁的监视不成比例地受到淋病和艾滋病毒的影响，并指导 开发新型抗菌剂以打击MDR-NG的努力。 公共卫生意义。这项研究将定义人咽中的大小和多样性AMR， 一个被认为在AMR-NG的出现中发挥着核心作用的解剖网站，并将提供新的见解 哪种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 洞悉AMR-NG的发展，如何制定策略以应满威胁的策略 AMR-NG和新型抗菌剂的发展。