Cancer drugs as drivers of antibiotic resistance

Abstract

Antibiotics are the cornerstone for modern medicine, and their introduction into clinical use has made common medical procedures such as surgeries and cancer chemotherapy possible. The consequences of antimicrobial resistance (AMR), if it continues to rise on a global scale at its current speed, are expected to be staggering. It is well-known that antibiotics drive the evolution and spread of AMR, but the extent to which non-antibiotic drugs can do the same remains largely unknown. In this thesis, I have investigated whether drugs used in cancer therapy may drive AMR evolution in the common gut bacteria Escherichia coli. I screened a panel of 73 oncology compounds against 11 common AMR mechanisms, looking for combinations where expressing AMR gives bacteria fitness advantages in the presence of antineoplastic agents. Of the 23 strongest combinations identified in the screen, an in-depth study looking into the effects on bacterial evolution and the underlying molecular mechanisms has been conducted for one agent. I show that the widely used cytotoxic drug methotrexate (MTX), used both in the treatment of cancer as well as for many autoimmune diseases, can not only cause high-level trimethoprim (TMP) resistance at a wide range of concentrations. Furthermore, I have demonstrated that selection for TMP resistance takes place at MTX concentrations well below the concentrations known to inhibit growth. This is especially problematic when TMP resistance is plasmid-mediated, as MTX exposure will then select for practically any AMR determinant co-expressed on the same plasmid. With this work, we provide valuable insights into the effects that drugs used in cancer chemotherapy have on AMR evolution. A better understanding of the drivers of resistance, especially those directly affecting vulnerable patient groups, is essential if we hope to curb the spread and evolution of AMR.