The need for new antibiotics that are active against multidrug resistant pathogens has created renewed interest in discovering antibiotics from sources of natural products. We have developed a new approach, bacterial cytological profiling (BCP), that 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. BCP is especially useful for identification of natural products in crude natural product extracts because it rapidly discriminates between antibiotics with different mechanisms of action (MOA). The BCP screening platform can detect nuisance compounds and multiple activities in partially purified or crude natural product extracts and it can detect active molecules at sub-inhibitory concentrations. The goal of this project is to develop a comprehensive natural product identification platform that combines BCP with genome mining methods to rapidly identify novel molecules and their biosynthetic gene clusters. Linnaeus Bioscience Inc. is a start up company founded to commercialize this technology and make it accessible on a fee for service basis to the pharmaceutical industry and the scientific community. This proposals describes a set of specific aims that will allow us to develop a simple, robust platform for discovering novel natural products active against drug resistant bacteria.
Public Health Relevance Statement: Public Health Relevance: We have developed a new approach called bacterial cytological profiling for screening for antibiotics and understanding their mechanisms of action. Bacterial cytological profiling can be used to identify natural products with antibacterial activites in crude natural product extracts and rapidly discriminates between different mechanisms of action. This approach can detect active molecules at sub--- inhibitory concentrations and can rapidly prioritize hits based on their likely mechanism of action. The goal of this project is to develop a natural product discovery platform that combines bacterial cytological profiling with genome mining techniques to more rapidly identify, characterize, and prioritize lead molecules from natural products.
NIH Spending Category: Antimicrobial Resistance; Biotechnology; Complementary and Alternative Medicine; Infectious Diseases
Project Terms: Actinobacteria class; Anti-Bacterial Agents; Antibiotic Therapy; Antibiotics; Antifungal Agents; base; Bioinformatics; Biological Factors; Businesses; Cells; Collaborations; Collection; Communities; Crude Extracts; Drug Industry; drug resistant bacteria; experience; Fee-for-Service Plans; Fluorescence Microscopy; Future; Gene Cluster; Genes; Genome; genome sequencing; Goals; Hour; Individual; interest; Lead; Mass Spectrum Analysis; Measures; Methods; Mining; multi-drug resistant pathogen; novel; novel strategies; overexpression; pathogen; Pathway interactions; programs; Property; public health relevance; screening; Source; Streptomyces; Techniques; Technology; tumor; Wor
