title: Collateral Resistance and Sensitivity Modulate Evolution of High-Level Resistance to Drug Combination Treatment in Staphylococcus aureus.
abstract: As drug-resistant pathogens continue to emerge, combination therapy will increasingly be relied upon to treat infections and to help combat further development of multidrug resistance. At present a dichotomy exists between clinical practice, which favors therapeutically synergistic combinations, and the scientific model emerging from in vitro experimental work, which maintains that this interaction provides greater selective pressure toward resistance development than other interaction types. We sought to extend the current paradigm, based on work below or near minimum inhibitory concentration levels, to reflect drug concentrations more likely to be encountered during treatment. We performed a series of adaptive evolution experiments using Staphylococcus aureus. Interestingly, no relationship between drug interaction type and resistance evolution was found as resistance increased significantly beyond wild-type levels. All drug combinations, irrespective of interaction types, effectively limited resistance evolution compared with monotreatment. Cross-resistance and collateral sensitivity were found to be important factors in the extent of resistance evolution toward a combination. Comparative genomic analyses revealed that resistance to drug combinations was mediated largely by mutations in the same genes as single-drug-evolved lineages highlighting the importance of the component drugs in determining the rate of resistance evolution. Results of this work suggest that the mechanisms of resistance to constituent drugs should be the focus of future resistance evolution work.
authors.affiliation: Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.
authors.forename: Mari
authors.initials: M
authors.lastname: Rodriguez de Evgrafov
authors.affiliation: Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.
authors.forename: Heidi
authors.initials: H
authors.lastname: Gumpert
authors.affiliation: Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Munck
authors.affiliation: Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.
authors.forename: Thomas T
authors.initials: TT
authors.lastname: Thomsen
authors.affiliation: Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Hørsholm, Denmark msom@bio.dtu.dk.
authors.forename: Morten O A
authors.initials: MO
authors.lastname: Sommer
mesh_terms: D004338:Drug Combinations; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D019143:Evolution, Molecular; D006801:Humans; D009154:Mutation; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000235:genetics* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects / Q000235:genetics* / Q000472:pathogenicity
chemical_list: D004338:Drug Combinations
keywords: antibiotic resistance; drug combinations; resistance evolution