Background Understanding drivers of antibiotic resistance evolution is fundamental for designing optimal treatment strategies and interventions to reduce the spread of antibiotic resistance. Various cytotoxic drugs used in cancer chemotherapy have antibacterial properties, but how bacterial populations are affected by these selective pressures is unknown. Here we test the hypothesis that the widely used cytotoxic drug methotrexate affects the evolution and selection of antibiotic resistance. Methods First, we determined methotrexate susceptibility (IC 90 ) and selective abilities in a collection of Escherichia coli and Klebsiella pneumoniae strains with and without pre-existing trimethoprim resistance determinants. We constructed fluorescently labelled pairs of E. coli MG1655 differing only in trimethoprim resistance determinants and determined the minimum selective concentrations of methotrexate using flow-cytometry. We further used an experimental evolution approach to investigate the effects of methotrexate on de novo trimethoprim resistance evolution. Findings We show that methotrexate can select for acquired trimethoprim resistance determinants located on the chromosome or a plasmid. Additionally, methotrexate co-selects for genetically linked resistance determinants when present together with trimethoprim resistance on a multi-drug resistance plasmid. These selective effects occur at concentrations 40- to >320-fold below the methotrexate minimal inhibitory concentration. Interpretation Our results strongly suggest a selective role of methotrexate for virtually any antibiotic resistance determinant when present together with trimethoprim resistance on a multi-drug resistance plasmid. The presented results may have significant implications for patient groups strongly depending on effective antibiotic treatment. Funding PJJ was supported by and the Northern Norway Regional Health Authority (SFP1292–16/HNF1586–21) and JPI-EC-AMR (Project 271,176/H10). DIA was supported by the (grant 2017–01,527). The publication charges for this article have been funded by a grant from the publication fund of UiT The Arctic University of Norway.
Many cytotoxic drugs used in cancer chemotherapy have antibacterial properties, but how bacterial populations are affected by these selective pressures is unknown. Here we test the hypothesis that the widely used cytotoxic drug methotrexate affects the evolution and selection of antibiotic resistance. We show that methotrexate can select for trimethoprim resistance determinants located on the chromosome or a plasmid. Additionally, methotrexate can co-select for virtually any antibiotic resistance determinant when present together with trimethoprim resistance on a multidrug-resistance clinical plasmid. These selective effects occur at concentrations 40- to >320-fold below the methotrexate minimal inhibitory concentration for Escherichia coli, suggesting a selective role of methotrexate chemotherapy for antibiotic resistance in patients that strongly depend on effective antibiotic treatment.One Sentence SummaryMethotrexate, a drug used in the treatments of cancers and inflammatory diseases, selects and co-selects antibiotic resistance determinants.
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