Identification of natural products targeting new pathways in bacteria

鉴定针对细菌新途径的天然产物

• 批准号: 9052699
• 负责人: JOSEPH A POGLIANO
• 金额: $ 69.92万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-12 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9052699
• 关键词: Affect; Anti-Bacterial Agents; Antibiotic Therapy; Antibiotics; Bacteria; Basic Science; Cells; Collection; Data; Data Set; Drug Targeting; Drug resistance; Escherichia coli; Fluorescence Microscopy; Future; Genes; Goals; Gram-Negative Bacteria; Gram-Positive Bacteria; Health; Hour; Individual; Lead; Measures; Multi-Drug Resistance; Natural Products; Organism; Pathway interactions; Peptide Hydrolases; Pharmaceutical Preparations; Proteins; Research; Resistance; Technology; Toxic effect; Wit; base; cellular targeting; combat; genome-wide; improved; insight; interest; killings; new therapeutic target; novel; novel strategies; pathogen; protein profiling; safety testing

DESCRIPTION (provided by applicant): We developed a new approach to facilitate identification of natural products with antibacterial activities that rapidly discriminates between different mechanisms of action (MOA). This approach, bacterial cytological profiling (BCP), uses quantitative fluorescence microscopy to measure the effects of antibiotic treatment on individual cells. Antibiotics that target different cellular pathways and different steps within a pathway generate unique cytological profiles, allowing identification of the likely MOA of new compounds within a few hours. We have now developed a complimentary approach that will allow us to identify molecules that inhibit proteins that are not currently targeted by antibacterial drugs. Ths approach, which we call rapid inhibition profiling (R.I.P.), entails the rapid, inducible depletionof a target protein, followed by cytological profiling. Our preliminary data demonstrate that depletion of a drug target by R.I.P. produces cytological effects identical to those produced by the corresponding drug. Furthermore, depletion of essential proteins that are not targeted by current antibacterial drugs produces novel cytological profiles that can be subsequently used to identify molecules that inhibit these new targets. We here propose to more fully develop the R.I.P. technology by employing it on a genome wide basis in E. coli and B. subtilis. This will create a comprehensive reference set of profiles associated with the inhibition of essential cellular pathways that are not the targets of current antibacterial drugs. The genome-wide R.I.P. analysis will also provide insight into the function of conserved genes and our preliminary data suggests that it will provide insight into proteins that coordinate two or more biosynthetic pathways, providing interesting starting points for future basic research. We will then use this more complete reference data set with BCP to screen a unique and diverse collection of natural product extracts to identify those that inhibit these new drug targets and kill multidrug resistant bacteria. Together with our collaborators at Fundaci¿n Medina, we will then purify and characterize our highest priority lead molecules (those that kill multidrug resistant bacteria) wit a goal of advancing them into toxicity trials.

描述（由申请人提供）：我们开发了一种新的方法来促进具有抗菌活性的天然产物的鉴定，可以快速区分