Weber Brent S, De Jong Aaron M, Guo Amelia B Y, Dharavath Srinivas, French Shawn, Fiebig-Comyn Aline A, Coombes Brian K, Magolan Jakob, Brown Eric D
Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON L8S 4L8, Canada.
Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON L8S 4L8, Canada; Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON L8S 4L8, Canada.
Cell Rep. 2020 Jul 21;32(3):107927. doi: 10.1016/j.celrep.2020.107927.
Antibiotics halt the growth of bacteria by targeting core, essential physiology that is required for life on standard microbiological media. Many more biochemical and virulence processes, however, are required for bacteria to cause infection in a host. Indeed, chemical inhibitors of the latter processes are overlooked using conventional antibiotic drug discovery approaches. Here, we use human blood serum as an alternative growth medium to explore new targets and compounds. High-throughput screening of genetic and chemical libraries identified compounds targeting biological activities required by Klebsiella pneumoniae to grow in serum, such as nucleobase biosynthesis and iron acquisition, and showed that serum can chemically transform compounds to reveal cryptic antibacterial activity. One of these compounds, ruthenium red, was effective in a rat bloodstream infection model. Our data demonstrate that human serum is an effective tool to find new chemical matter to address the current antibiotic resistance crisis.
抗生素通过靶向标准微生物培养基上生命所需的核心、基本生理过程来阻止细菌生长。然而，细菌要在宿主体内引发感染还需要更多的生化和毒力过程。事实上，使用传统的抗生素药物发现方法会忽略后一类过程的化学抑制剂。在此，我们使用人血清作为替代生长培养基来探索新的靶点和化合物。对基因库和化学库进行高通量筛选，确定了靶向肺炎克雷伯菌在血清中生长所需生物活性的化合物，如核碱基生物合成和铁摄取，并表明血清可对化合物进行化学转化以揭示潜在的抗菌活性。其中一种化合物钌红，在大鼠血流感染模型中有效。我们的数据表明，人血清是寻找新化学物质以应对当前抗生素耐药性危机的有效工具。
