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

项目总结/摘要 耐利福平结核病（RR-TB）仍然是全球公共卫生危机。分子TB检测试剂盒，如Xpert 已导致RR-TB病例检出率大幅增加，全球估计需求持续扩大， 新的治疗方法。大量的财政和科学资源被用于研究新的 但优化和扩大疗程较短的全口服RR-TB方案的努力受到阻碍 这主要是由于缺乏可用性和获得这些表型或分子易感性测试， 剂.常规表型药敏试验的长期关键障碍包括 周转时间和基础设施要求，妨碍了有效的规模扩大，大大有助于 耐药结核病诊断差距。患者往往致力于数月的无效治疗，导致收购 通过选择性药物压力和更差的临床结果进一步耐药。我们的目标是提出 这项工作是通过战略性和基于证据的基因组学工具的使用， 负荷设置。我们将利用与国际非营利组织的合作，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检测转化为 具有成本效益的手持式纳米孔测序平台（Aim 1，近临床解决方案）; 在两个不同地理区域的患者治疗过程的早期对患者样本进行测序， RR-TB和HIV流行病（目标2，集中解决方案）。这些努力将把现代病原体 基因组学对人口的好处，并有助于延长有效寿命的艰苦斗争的新的， 被重新利用的抗结核药物

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.