The chemotherapeutic drug methotrexate selects for antibiotic resistance

• Published in: EBioMedicine
• Main Authors: Jónína S. Guðmundsdóttir, Elizabeth G.A. Fredheim, Catharina I.M. Koumans, Joachim Hegstad, Po-Cheng Tang, Dan I. Andersson, Ørjan Samuelsen, Pål J. Johnsen
• Format: Article in Journal/Newspaper
• Language: English
• Published: Elsevier 2021
• Subjects: Chemotherapeutic drugs; E. coli; Antibiotic resistance; Methotrexate; Resistance evolution; Medicine; R; Medicine (General); R5-920; Arctic; Norway; Northern Norway; Arctic University of Norway; UiT The Arctic University of Norway
• Online Access: https://doi.org/10.1016/j.ebiom.2021.103742; https://doaj.org/article/ec68090bd0bc46cbb788a8646dfb8f2d

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 (IC90) 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 UiT The Arctic University of Norway and the Northern Norway Regional Health Authority (SFP1292–16/HNF1586–21) and JPI-EC-AMR (Project 271,176/H10). DIA was supported ...