Harvard-wide Program on Antibiotic Resistance

摘要 哈佛大学抗生素耐药性项目的目标是应用创新的先进技术 开发治疗多药耐药主要原因的新战略的技术 葡萄球菌和肠球菌引起的医院相关性感染。虽然备受关注 已经适当地关注了最近出现的泛耐药革兰氏阴性细菌， 葡萄球菌和肠球菌仍然是发病率和死亡率的主要原因。 与多重耐药ESKAPE病原体感染有关，突显了 目前的治疗方法。这个由多名调查员参与的项目汇集了来自不同领域的专家 从数学和系统生物学到传染病临床医生，并创造了一个 为他们提供协作和协同工作的基础设施，带来新的见解和 有能力解决主要的公共卫生危机--抗生素耐药感染。 在上一次支持期间，通过按下 包络新技术，包括最先进的高通量突变和 尚未对这些微生物进行比较基因组分析。在拟议的续订中 在此期间，这些技术将与微流控技术的最新进展和单一 细胞延时成像，揭示这些细菌的新脆弱性，以供新的靶向 化合物。开发和使用创新屏幕，以降低目标风险并揭开面纱 新的机遇，为治疗提供新的、更有效的化合物设计 耐多药葡萄球菌和肠球菌感染。填补关键的知识空白 与微生物在抗生素挑战中存活的各种机制有关，包括 随机进入交替生长状态并通过以下方式主动降低药物浓度 Exlux，使该计划在其方法上异常全面。最后，这个项目 通过建立和促进信息交流，积极与社会分享其成果 以及与其他学术和行业科学家的联系，并通过确保重要的抗生素 发现知识被保存下来，并传递给下一代科学家。结果 关于内部和外部协同效应，哈佛大学范围内的抗生素计划的影响 阻力比通过个人研究努力否则可能的阻力要大得多。

SUMMARY The goal of the Harvard-wide Program on Antibiotic Resistance is to apply innovative advanced technologies to developing new strategies for treating leading causes of multidrug resistant hospital-associated infection caused by staphylococci and enterococci. Although much attention has appropriately been focused on the recent emergence of pan-resistant gram negative bacteria, staphylococci and enterococci remain the leading causes of both morbidity and mortality associated with infection by multidrug resistant ESKAPE pathogens, highlighting the limitation of current therapeutic approaches. This multi-investigator project brings together experts from fields ranging from mathematics and systems biology to infectious disease clinicians, and creates an infrastructure for them to work collaboratively and synergistically, bringing new insights and capabilities to bear in solving the leading public health crisis of antibiotic resistant infection. Important discoveries and advances were made in the previous period of support by pressing the envelope with new technologies, including the most advanced high throughput mutational and comparative genomic analyses yet conducted on these microbes. In the proposed continuation period, these technologies will be combined with the latest advances in microfluidics and single cell time lapse imaging, to reveal new vulnerabilities of these bacteria for targeting by new compounds. The development and use of innovative screens that de-risk targets as well as unveil new opportunities, inform the design of new and more efficacious compounds for treating multidrug resistant staphylococcal and enterococcal infection. Filling critical knowledge gaps related to the various mechanisms by which microbes survive antibiotic challenge, including stochastic entry into alternate growth states and actively reducing drug concentration through efflux, make this program exceptionally comprehensive in its approach. Finally, this project actively shares its results with the community by establishing and promoting information exchange and networking with other academic and industry scientists, and by ensuring important antibiotic discovery knowledge is preserved and transmitted to the next generation of scientists. As a result of internal and external synergies, the impact of the Harvard-wide Program on Antibiotic Resistance is much greater than would otherwise be possible through individual research efforts.