Harvard-wide Program on Antibiotic Resistance

总结 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， 开发新的策略来治疗多药耐药的主要原因 由葡萄球菌和肠球菌引起医院相关感染。虽然很多关注 已经适当地集中在最近出现的泛耐药革兰氏阴性细菌上， 葡萄球菌和肠球菌仍然是发病率和死亡率的主要原因 与多药耐药ESKAPE病原体感染相关，突出了 目前的治疗方法。这个多研究者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， 基础设施，使他们能够协同工作，带来新的见解， 在解决抗生素耐药性感染这一主要公共卫生危机方面， 在前一个支持期内，通过推动 信封与新技术，包括最先进的高通量突变和 对这些微生物进行了比较基因组分析。在拟议的续设中， 在此期间，这些技术将与微流体和单细胞生物技术的最新进展相结合。 细胞时间推移成像，以揭示这些细菌的新弱点， 化合物.开发和使用创新的屏幕，消除风险目标，并揭示 新的机会，通知设计新的和更有效的化合物，用于治疗 多重耐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 随机进入交替的生长状态，并通过 外排，使这个计划在其方法非常全面。最后，这个项目 通过建立和促进信息交流，积极与社区分享其成果 并与其他学术和工业科学家建立联系， 发现的知识被保存下来并传给下一代科学家。因此 内部和外部的协同作用，哈佛大学抗生素计划的影响， 抵抗力比通过个人研究努力所能达到的要大得多。

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.