Combatting antibiotic resistance with synthetic biology technologies

利用合成生物学技术对抗抗生素耐药性

• 批准号: 9167953
• 负责人: Ahmad Samir Khalil
• 金额: $ 247.24万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9167953
• 关键词: Accounting; Antibiotic Resistance; Antibiotic susceptibility; Antibiotics; Antimicrobial Resistance; Bacterial Infections; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Characteristics; Clinic; Clinical; Detection; Diagnosis; Diagnostic; Diagnostic Procedure; Drug resistance; Engineering; Freeze Drying; Genetic; Gold; Gonorrhea; Health; Hour; Infection; Messenger RNA; Methods; Microbe; Molecular; Molecular Profiling; Neisseria gonorrhoeae; Organism; Paper; Performance; Phenotype; Population; Predisposition; RNA; Resistance; Risk; Sampling; System; Techniques; Technology; Testing; Time; Treatment Failure; Work; bacterial resistance; base; cell growth; clinically relevant; combat; cost; disorder prevention; drug resistant bacteria; effective therapy; innovation; microorganism; new technology; novel diagnostics; pathogen; prevent; sensor; solid state; synthetic biology

PROJECT SUMMARY / ABSTRACT The emergence of antimicrobial resistance is one of the most serious health threats to our entire population. Infections from resistant bacteria are now too common, and some pathogens have become resistant to multiple antibiotic classes. The Centers for Disease Control and Prevention (CDC) recently estimated that drug-resistant bacteria account for more than 2 million illnesses and over 23,000 deaths every year in the U.S. With rising rates of drug-resistant infections, there is pressing need for new diagnostic methods that can rapidly determine the most effective therapy for an infection. Unfortunately, the current method for performing antibiotic susceptibility testing (AST) involves growing microorganisms from clinical samples and determining their sensitivity to antibiotics through cell growth. This “gold standard” technique is extremely time-consuming (minimum 48-72 hours) and can result in significant delays in appropriate therapy, prolonged illness, greater risk of death, inappropriate antibiotic use, and increased spread of resistance. For some infections like gonorrhea, AST is not even performed in the clinic and instead inferred based on treatment failure. In short, it is imperative that new strategies are developed to rapidly diagnose and prevent the amplification of drug resistance. Antibiotic exposure can trigger the expression of a signature set of mRNAs in susceptible microbes in as rapidly as a few minutes, raising the exciting possibility of using RNA detection – not cell growth – as a new means for rapid, phenotype-based AST. We will develop innovative RNA sensor technology that evaluates these molecular signatures within a clinically-relevant, low-cost, and easy-to-use diagnostic platform. To achieve this, we will use synthetic biology approaches to engineer highly-sensitive genetic sensors of mRNA. These sensors will be deployed in cell-free expression systems that can be arrayed and freeze-dried onto low-cost, solid-state substrates like paper. The result will be a new class of antibiotic diagnostics with ideal performance, storage, and distribution characteristics. The RNA sensor technology will be developed and validated with high priority bacterial organisms. Notably, we will, for the first time, define RNA signatures of susceptibility for N. gonorrhoeae, which the CDC recently elevated as a major cause for concern in the U.S. and for which AST capabilities do not currently existing in the clinical setting. This work will usher in a new technology for rapidly diagnosing antibiotic resistance, with the potential to transform the management of today's growing antimicrobial resistance problem.

项目摘要 /摘要 抗菌素抵抗的出现是对我们整个人群最严重的健康威胁之一。 抗性细菌感染现在太常见了，有些病原体已经抗性 多种抗生素类。疾病控制与预防中心（CDC）最近估计 耐药细菌在美国每年造成超过200万疾病和23,000多人死亡 随着耐药性感染率的上升，需要急需新的诊断方法 确定感染最有效的疗法。不幸的是，当前执行的方法 抗生素易感性测试（AST）涉及临床样品中种植的微生物并确定 它们通过细胞生长对抗生素的敏感性。这种“黄金标准”技术非常耗时 （至少48-72小时），并可能导致适当的治疗，长期疾病，更大的延迟 死亡的风险，不适当的抗生素使用以及耐药性的扩散增加。对于某些感染 Gonorrhea，AST甚至没有在诊所进行，而是根据治疗失败推断。简而言之，它 必须制定新策略来快速诊断和防止药物扩增 反抗。抗生素暴露会触发易感微生物中的签名mRNA的表达 在几分钟的迅速中，提高了使用RNA检测而不是细胞生长的令人兴奋的可能性 基于快速，基于表型的AST的新手段。我们将开发创新的RNA传感器技术 在临床上，低成本且易于使用的诊断平台中评估这些分子特征。 为此，我们将使用合成生物学方法来设计高度敏感的遗传传感器 mRNA。这些传感器将部署在无细胞的表达系统中 在低成本的固态基材上，如纸。结果将是一类新的抗生素诊断。 理想的性能，存储和分销特征。 RNA传感器技术将开发，并且 用高优先级细菌验证。值得注意的是，我们将第一次定义RNA签名 CDC最近将其作为美国关注的主要原因提高了淋病的敏感性 并且在临床环境中目前不存在AST功能。这项工作将引入新的 快速诊断性抗生素抗性的技术，有可能改变管理 当今日益增长的抗菌素抗性问题。