title: A cell-based approach to characterize antimicrobial compounds through kinetic dose response.
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.
authors.affiliation: Michael G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8N 3ZS, Canada.
authors.forename: Craig R
authors.initials: CR
authors.lastname: MacNair
authors.affiliation: Michael G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8N 3ZS, Canada.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Stokes
authors.affiliation: Michael G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8N 3ZS, Canada.
authors.forename: Shawn
authors.initials: S
authors.lastname: French
authors.affiliation: Michael G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8N 3ZS, Canada.
authors.forename: Cullen L
authors.initials: CL
authors.lastname: Myers
authors.affiliation: Michael G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8N 3ZS, Canada.
authors.forename: Kali R
authors.initials: KR
authors.lastname: Iyer
authors.affiliation: Michael G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8N 3ZS, Canada. Electronic address: ebrown@mcmaster.ca.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Brown
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000191:economics / Q000494:pharmacology*; D001419:Bacteria / Q000166:cytology / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D054852:Small Molecule Libraries / Q000737:chemistry / Q000191:economics / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D054852:Small Molecule Libraries
keywords: Antibiotic discovery; Dose response; High-throughput screening; Hit to lead