Handheld and population-based sequencing for rapid detection of new and repurposed drug resistance in M. tuberculosis

项目摘要/摘要 利福平耐药结核病(RR-TB)仍然是一种全球公共卫生危机。Xpert等分子结核检测方法 已导致RR-TB病例检测大幅增加，全球估计需求持续扩大 更新的治疗方法。大量的财政和科学资源被用于研究新的 和重新调整用途的药物，但优化和扩大较短疗程、全口服RR-TB方案的努力受到阻碍 重要的是缺乏对这些病毒的表型或分子敏感性测试 探员们。长期存在的常规表型药敏试验的关键障碍包括 周转时间和基础设施要求，阻碍了高效的纵向扩展，大大促进了 DR-TB的诊断差距。患者经常接受数月无效的治疗，导致感染 通过选择性药物压力和更差的临床结果进一步耐药。我们提出的目标是 这项工作是通过战略性和循证地使用基因组学工具来改善患者的预后 负担设置。我们将利用与国际非营利组织、南非MRC- 资助的队列和商业合作伙伴将我们建立的靶向深度测序分析转化为 成本效益高的手持式纳米孔测序平台(目标1，接近临床的解决方案)；以及 在两个不同的地理区域对治疗过程中的早期患者样本进行排序 结核病和艾滋病毒流行(目标2，集中解决方案)。这些努力将把现代病原体 基因组学为人口造福，并有助于延长艰苦斗争的新的和 调整了抗结核药物的用途。

PROJECT SUMMARY / ABSTRACT Rifampin-resistant tuberculosis (RR-TB) remains a global public health crisis. Molecular TB assays such as Xpert have led to dramatic increases in RR-TB case detection and ongoing expansion of the global estimated need for newer treatments. Tremendous financial and scientific resources are directed toward the investigation of new and repurposed drugs, but efforts to optimize and scale-up shorter course, all-oral RR-TB regimens are hindered significantly by the scarcity of availability and access to phenotypic or molecular susceptibility testing for these agents. Longstanding critical barriers of routine phenotypic drug susceptibility testing include prolonged turnaround time and infrastructure requirements that preclude efficient scale-up, contributing significantly to the DR-TB diagnostic gap. Patients are often committed to months of ineffective treatments, leading to acquisition of further drug resistance through selective drug pressure and worse clinical outcomes. Our goal in proposing this work is to improve patient outcomes through strategic and evidence-based use of genomics tools in high burden settings. We will leverage collaborations with international non-profit organizations, a South African MRC- funded cohort, and commercial partners to translate our established targeted deep sequencing assay onto a cost-efficient, handheld nanopore-based sequencing platform (Aim 1, near-clinic solution); and prospectively sequence patient samples early in the course of their treatment in two diverse geographic regions with differing RR-TB and HIV epidemics (Aim 2, centralized solution). These efforts will translate modern-day pathogen genomics into population benefits and contribute to extending the effective lifespan of hard fought new and repurposed anti-TB drugs.