A cell-based approach to characterize antimicrobial compounds through kinetic dose response |
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Institution: | 1. Department of Epidemiology and Biostatistics, The George Washington University, Washington, DC;2. Department of Medicine, Alpert School of Medicine, Brown University, Providence, RI;3. Department of Obstetrics and Gynecology, Alpert School of Medicine, Brown University, Providence, RI;1. Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, United States;2. Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, United States;3. Natural Products Library Initiative at The Scripps Research Institute, The Scripps Research Institute, Jupiter, FL 33458, United States |
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Abstract: | The rapid spread of antibiotic resistance has created a pressing need for the development of novel drug screening platforms. Herein, we report on the use of cell-based kinetic dose response curves for small molecule characterization in antibiotic discovery efforts. Kinetically monitoring bacterial growth at sub-inhibitory concentrations of antimicrobial small molecules generates unique dose response profiles. We show that clustering of profiles by growth characteristics can classify antibiotics by mechanism of action. Furthermore, changes in growth kinetics have the potential to offer insight into the mechanistic action of novel molecules and can be used to predict off-target effects generated through structure–activity relationship studies. Kinetic dose response also allows for detection of unstable compounds early in the lead development process. We propose that this kinetic approach is a rapid and cost-effective means to gather critical information on antimicrobial small molecules during the hit selection and lead development pipeline. |
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Keywords: | Antibiotic discovery High-throughput screening Hit to lead Dose response |
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