title: Alternating antibiotic treatments constrain evolutionary paths to multidrug resistance.
abstract: Alternating antibiotic therapy, in which pairs of drugs are cycled during treatment, has been suggested as a means to inhibit the evolution of de novo resistance while avoiding the toxicity associated with more traditional combination therapy. However, it remains unclear under which conditions and by what means such alternating treatments impede the evolution of resistance. Here, we tracked multistep evolution of resistance in replicate populations of Staphylococcus aureus during 22 d of continuously increasing single-, mixed-, and alternating-drug treatment. In all three tested drug pairs, the alternating treatment reduced the overall rate of resistance by slowing the acquisition of resistance to one of the two component drugs, sometimes as effectively as mixed treatment. This slower rate of evolution is reflected in the genome-wide mutational profiles; under alternating treatments, bacteria acquire mutations in different genes than under corresponding single-drug treatments. To test whether this observed constraint on adaptive paths reflects trade-offs in which resistance to one drug is accompanied by sensitivity to a second drug, we profiled many single-step mutants for cross-resistance. Indeed, the average cross-resistance of single-step mutants can help predict whether or not evolution was slower in alternating drugs. Together, these results show that despite the complex evolutionary landscape of multidrug resistance, alternating-drug therapy can slow evolution by constraining the mutational paths toward resistance.
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA 02115; and.
authors.forename: Seungsoo
authors.identifier: http://orcid.org/0000-0002-5559-5289
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA 02115; and.
authors.forename: Tami D
authors.initials: TD
authors.lastname: Lieberman
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA 02115; and Faculty of Biology, Technion - Israel Institute of Technology, Technion City, Haifa 3200003, Israel roy_kishony@hms.harvard.edu.
authors.forename: Roy
authors.initials: R
authors.lastname: Kishony
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004334:Drug Administration Schedule; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics*; D004358:Drug Therapy / Q000379:methods; D004359:Drug Therapy, Combination; D019143:Evolution, Molecular; D016680:Genome, Bacterial / Q000235:genetics; D006801:Humans; D009154:Mutation / Q000187:drug effects; D059645:Mutation Rate; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics*; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents
keywords: antibiotic resistance; collateral sensitivity; drug cycling; experimental evolution; multidrug therapy