title: Classic reaction kinetics can explain complex patterns of antibiotic action.
abstract: Finding optimal dosing strategies for treating bacterial infections is extremely difficult, and improving therapy requires costly and time-intensive experiments. To date, an incomplete mechanistic understanding of drug effects has limited our ability to make accurate quantitative predictions of drug-mediated bacterial killing and impeded the rational design of antibiotic treatment strategies. Three poorly understood phenomena complicate predictions of antibiotic activity: post-antibiotic growth suppression, density-dependent antibiotic effects, and persister cell formation. We show that chemical binding kinetics alone are sufficient to explain these three phenomena, using single-cell data and time-kill curves of Escherichia coli and Vibrio cholerae exposed to a variety of antibiotics in combination with a theoretical model that links chemical reaction kinetics to bacterial population biology. Our model reproduces existing observations, has a high predictive power across different experimental setups (R(2) = 0.86), and makes several testable predictions, which we verified in new experiments and by analyzing published data from a clinical trial on tuberculosis therapy. Although a variety of biological mechanisms have previously been invoked to explain post-antibiotic growth suppression, density-dependent antibiotic effects, and especially persister cell formation, our findings reveal that a simple model that considers only binding kinetics provides a parsimonious and unifying explanation for these three complex, phenotypically distinct behaviours. Current antibiotic and other chemotherapeutic regimens are often based on trial and error or expert opinion. Our "chemical reaction kinetics"-based approach may inform new strategies, which are based on rational design.
authors.affiliation: Division of Global Health Equity, Brigham and Women's Hospital and Harvard Medical School, 641 Huntington Avenue, Boston, MA 02115, USA. Department of Epidemiology of Microbial Diseases, Yale School of Public Health, 60 College Street, New Haven, CT 06510, USA. pzw@daad-alumni.de.
authors.forename: Pia
authors.initials: P
authors.lastname: Abel Zur Wiesch
authors.affiliation: Division of Infectious Diseases, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA. Department of Pharmacy, UiT, The Arctic University of Norway, 9037 Tromsø, Norway.
authors.forename: Sören
authors.initials: S
authors.lastname: Abel
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Retzius väg 8, 17177 Stockholm, Sweden.
authors.forename: Spyridon
authors.initials: S
authors.lastname: Gkotzis
authors.affiliation: Institute of Integrative Biology, ETH Zürich, Universitätsstrasse 16, 8092 Zürich, Switzerland. Department of Environmental Microbiology, EAWAG, Überlandstrasse 133, 8600 Dübendorf, Switzerland.
authors.forename: Paolo
authors.initials: P
authors.lastname: Ocampo
authors.affiliation: School of Biological Sciences, University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Jan
authors.initials: J
authors.lastname: Engelstädter
authors.affiliation: School of Chemistry, University of Glasgow, University Avenue, Glasgow G12 8QQ, UK.
authors.forename: Trevor
authors.initials: T
authors.lastname: Hinkley
authors.affiliation: Institute of Medical Virology, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Carsten
authors.initials: C
authors.lastname: Magnus
authors.affiliation: Division of Infectious Diseases, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA. Howard Hughes Medical Institute, 181 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Waldor
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Retzius väg 8, 17177 Stockholm, Sweden.
authors.forename: Klas
authors.initials: K
authors.lastname: Udekwu
authors.affiliation: Division of Global Health Equity, Brigham and Women's Hospital and Harvard Medical School, 641 Huntington Avenue, Boston, MA 02115, USA. Department of Epidemiology of Microbial Diseases, Yale School of Public Health, 60 College Street, New Haven, CT 06510, USA. Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA.
authors.forename: Ted
authors.initials: T
authors.lastname: Cohen
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D014734:Vibrio cholerae / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents