Attacking failure of antibiotic treatment by targeting antimicrobial resistance enabler cell-states

通过针对抗生素耐药性细胞状态来应对抗生素治疗的失败

• 批准号: 10703342
• 负责人: Vaughn Cooper
• 金额: $ 257.16万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-12 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10703342
• 关键词: Acinetobacter baumannii; Antibiotic Resistance; Antibiotic Therapy; Antibiotic susceptibility; Antibiotics; Antimicrobial Resistance; Bacterial Infections; Bioinformatics; Biological Models; Cells; Characteristics; Collaborations; Collection; Complex; Data; Detection; Development; Diagnostic; Drug Targeting; Early Diagnosis; Environment; Equation; Etiology; Evolution; Failure; Frequencies; Genetic; Genomics; Genotype; Goals; Heel; Immune system; In Vitro; Individual; Infection; Intermediate resistance; Libraries; Maps; Minority; Mutation; Organism; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Population; Predisposition; Principal Investigator; Process; Recording of previous events; Regimen; Resistance; Resistance development; Role; Running; Sampling; Side; Source; Streptococcus pneumoniae; Stress; Testing; Treatment Failure; Treatment Protocols; Variant; Work; antimicrobial; arms race; blind; cost; design; diagnostic assay; diagnostic strategy; drug discovery; emerging antibiotic resistance; emerging antimicrobial resistance; fitness; genetic association; genomic tools; in vivo; innovation; member; novel diagnostics; novel strategies; novel therapeutics; pathogenic bacteria; pharmacokinetics and pharmacodynamics; pressure; prevent; resistance gene; resistance mutation; synergism; transcriptional reprogramming; transcriptome sequencing

SUMMARY Deployment of new antimicrobials is promptly circumvented by the rapid evolution of resistance, underscoring the critical need for new strategies to stay ahead in the arms-race against bacterial pathogens. Developing a detailed understanding of the circumstances as well as genetic and mechanistic basis for which antibiotic resistance develops provides opportunities for pre-emptively subverting this process. While infections caused by organisms harboring antimicrobial resistance (AMR) genes are a major cause of antibiotic treatment failure (ATF), ATF frequently occurs when the etiological agents are not AMR by traditional susceptibility testing. It is becoming increasingly recognized that transient cell-states such as tolerance, persistence and hetero-resistance are critical drivers underlying treatment failure. However, there is a paucity of data with regards to the genetic and mechanistic basis for these cell-states as well as a lack of diagnostic-detection approaches. ATF cell-states initially exist as minority variants within a population and display a transient phenotype that tends to dissipate as the stress subsides, making them challenging to detect and consequently missed in current diagnostic assays. These enabler cell-states remain mechanistically poorly understood and seem to preferentially arise during fluctuating treatment regimens, for instance caused by a drug’s PK/PD characteristics, whereby ATF cell-states can drive the re-emergence of the (susceptible) bacterial infection after antibiotic pressure wanes. Importantly, this creates opportunities where multi-step high-level resistance mutations are given an extended opportunity to emerge. Therefore, because antibiotic resistant variants often follow closely on the heels of the occurrence of ATF cell-states, these cell-states can be viewed as enablers of antibiotic treatment failure and AMR. This proposal focuses on untangling the importance of ATF cell-states in the emergence of antibiotic resistance and treatment failure, and designs new approaches and strategies to identify, track and target them. The main team consists of 4 principal investigators that have a very successful collaboration history. Together they will work on 5 challenges distributed across 3 projects and supported by an administrative and a genomics and bioinformatics core. In Challenge: 1) the full profile of possible genetic pathways that can induce ATF cell-states is determined; 2) treatment regimens that drive the emergence of ATF-cell states are determined; 3) it is determined how ATF cell-states enable the emergence of AMR; 4) drugs and compounds are screened for, that target ATF cell-state collateral sensitivities; 5) a computational deconvolution approach is developed that predicts the presence and frequency of ATF cell-states in a complex bacterial population. Overall this proposal contains a collection of conceptually and technically innovative aspects that are geared towards understating the genetic mechanisms and evolutionary forces that sit at the root of the emergence of resistance, with the ultimate goal to design new diagnostics and antimicrobial strategies that can slow or even stop the current endless arms-race “that takes all the running we can do, to keep in the same place”.

概括 抗药性的快速发展，强调，新抗微生物的部署很快就会避免 对新策略的关键需求，以抵御细菌病原体的武器。开发 详细了解抗生素的情况以及遗传和机械基础 阻力发展为预先颠覆这一过程提供了机会。而感染是由 具有抗菌耐药性（AMR）基因的生物是抗生素治疗衰竭（ATF）的主要原因， 当传统的敏感性测试不是AMR时，经常发生ATF。它正在变成 越来越认识到暂时性细胞园，例如耐受性，持久性和异抗性是至关重要的 驱动因素的驱动因素失败。但是，关于遗传和 这些细胞群的机械基础以及缺乏诊断检测方法。 ATF细胞态 最初以人口中的少数族裔形式存在，并显示出瞬息万变的瞬态表型 压力减轻，使它们挑战在当前的诊断测定中检测并因此错过。 这些促进剂细胞园​​在机械上保持不当理解，并且似乎优先出现 例如，由药物的PK/PD特征引起的波动治疗方案，ATF细胞态 抗生素压力减弱后（易感）细菌感染的重新出现。重要的是， 这创造了机会，在多步高级阻力突变中有一个扩展的机会 出现。因此，由于抗生素耐药性变体通常紧随其后紧随其后。 ATF细胞园，这些细胞园可以被视为抗生素治疗衰竭和AMR的推动因素。这 提案的重点是解开ATF细胞态在抗生素出现中的重要性 抵抗和治疗失败，并设计新的方法和策略来识别，跟踪和目标 他们。主要团队由4位具有非常成功的合作历史的主要调查员组成。 他们将共同处理在3个项目中分发的5个挑战，并在行政和 基因组学和生物信息学核心。在挑战中：1）可能诱导的遗传途径的完整概况 确定ATF细胞状态； 2）确定推动ATF细胞状态出现的治疗方案； 3）确定了ATF细胞态如何实现AMR的出现； 4）筛选药物和化合物 因为，该靶向ATF细胞状态副灵敏度； 5）开发了一种计算反卷积方法 这可以预测复杂细菌种群中ATF细胞园的存在和频率。总的来说 提案包含概念和技术创新方面的集合，这些方面旨在 低估了位于抗性出现根源的遗传机制和进化力 最终目标是设计新的诊断和抗菌策略，这些策略可以放慢甚至阻止 当前无尽的武器竞赛“这需要我们可以做的所有跑步，以保持在同一位置”。