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.
MacNair CR, Stokes JM, French S, Myers CL, Iyer KR, Brown ED.
Bioorg Med Chem. 2016 Dec 15;24(24):6315-6319. doi: 10.1016/j.bmc.2016.09.053.