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.

项目总结/文摘