Abstract
BackgroundUnderstanding 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.MethodsFirst, 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.FindingsWe 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.InterpretationOur 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.FundingPJJ was supported by 10.13039/100007465UiT 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 by the 10.13039/501100004359Swedish Research Council (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.
Highlights
Global overuse and misuse of antimicrobial drugs in combination with dwindling discovery rates of new antimicrobials have led to the current antibiotic resistance crisis [1]
We show that MTX selects for acquired bacterial TMP resistance (TMPR) and coselects for other antibiotic resistance determinants when co-residing on a mobile genetic element
MTX can mediate selection of any antibiotic resistance determinant in E. coli when TMPR is co-localized on a mobile genetic element across a wide concentration gradient
Summary
Global overuse and misuse of antimicrobial drugs in combination with dwindling discovery rates of new antimicrobials have led to the current antibiotic resistance crisis [1]. The existing literature shows that many cytotoxic drugs, including methotrexate, a widely used drug for treatment of cancer and inflammatory diseases inhibit bacterial growth. Many of those drugs are known to share molecular targets with commonly used antibiotics (e.g. methotrexate and trimethoprim). 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.
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