title: Isolated cell behavior drives the evolution of antibiotic resistance.
abstract: Bacterial antibiotic resistance is typically quantified by the minimum inhibitory concentration (MIC), which is defined as the minimal concentration of antibiotic that inhibits bacterial growth starting from a standard cell density. However, when antibiotic resistance is mediated by degradation, the collective inactivation of antibiotic by the bacterial population can cause the measured MIC to depend strongly on the initial cell density. In cases where this inoculum effect is strong, the relationship between MIC and bacterial fitness in the antibiotic is not well defined. Here, we demonstrate that the resistance of a single, isolated cell-which we call the single-cell MIC (scMIC)-provides a superior metric for quantifying antibiotic resistance. Unlike the MIC, we find that the scMIC predicts the direction of selection and also specifies the antibiotic concentration at which selection begins to favor new mutants. Understanding the cooperative nature of bacterial growth in antibiotics is therefore essential in predicting the evolution of antibiotic resistance.
authors.affiliation: Department of Physics, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Artemova
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
authors.forename: Ylaine
authors.initials: Y
authors.lastname: Gerardin
authors.affiliation: Department of Physics, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Carmel
authors.initials: C
authors.lastname: Dudley
authors.affiliation: Department of Physics, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Vega
authors.affiliation: Department of Physics, Massachusetts Institute of Technology, Cambridge, MA, USA gore@mit.edu.
authors.forename: Jeff
authors.initials: J
authors.lastname: Gore
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002439:Cefotaxime / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development*; D019143:Evolution, Molecular; D056084:Genetic Fitness; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D059010:Single-Cell Analysis / Q000379:methods
chemical_list: D000900:Anti-Bacterial Agents; D002439:Cefotaxime
keywords: antibiotic resistance; beta‐lactamase; cooperative growth; evolution