The chemotherapeutic drug methotrexate selects for antibiotic resistance

Guðmundsdóttir, Jónína Sæunn; Fredheim, Elizabeth G. Aarag; Koumans, Catharina I.M.; Hegstad, Joachim; Tang, Po-Cheng; Andersson, Dan I.; Samuelsen, Ørjan; Johnsen, Pål Jarle

doi:10.1101/2020.11.12.378059

Cited by 2 publications

(2 citation statements)

References 32 publications

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“…NADs can decrease the growth of both human gut strains (2), pathogens (3), and clinical and lab strains of bacteria (4)(5)(6). However, some NADs can also increase horizontal gene transfer (HGT) rates between bacterial species through transformation (7,8), and conjugation (9)(10)(11), as well as selecting for antibiotic resistance through increasing mutation rates (12)(13)(14)(15). Therefore, there are concerns that NADs may select for antimicrobial resistance (AMR).…”

Section: Introductionmentioning

confidence: 99%

Antimicrobial effects, and selection for AMR by non-antibiotic drugs on bacterial communities

Hayes,

Zhang,

Feil

et al. 2024

Preprint

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Antimicrobial resistance (AMR) is a major threat to human, veterinary, and agricultural health. AMR can be directly selected for by antibiotics, and indirectly co-selected for by biocides and metals. Some evidence suggests that non-antibiotic drugs (NADs) can co-select for AMR, but previous work focused on exposing single model bacterial species to predominately high concentrations of NADs. Here, we determined the antimicrobial effect and selective potential of three commonly used NADs against a complex bacterial community using a combination of culture based, metagenomic, and metratranscriptomic approaches. We found that three of five NADs tested on growth significantly reduced growth of a bacterial community, although only one (17-β-estradiol) selected for an AMR marker using qPCR. Whole metagenome sequencing indicated that there was no clear strong selection by NADs for antibiotic resistance genes, nor effects on community composition. However, some changes in relative abundance of metal resistance genes were observed after exposure to diclofenac, metformin, and 17-β-estradiol. Together, these results indicate that the NADs tested likely do not strongly select for AMR at both clinically and environmentally relevant concentrations.

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Section: Introductionmentioning

confidence: 99%

Antimicrobial effects, and selection for AMR by non-antibiotic drugs on bacterial communities

Hayes,

Zhang,

Feil

et al. 2024

Preprint

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“…We chose MTX as our antifolate of choice for this screening as S. cerevisiae has been previously reported as being insensitive to TMP through mechanisms not directly involving the DHFR [45]. However, a recent study has associated the exposure of MTX in bacteria to both the selection for, and de novo evolution of, TMP resistance in bacteria [46]. Additionally, MTX is often used to treat auto-immune diseases, and can act as an immunosuppressant [47], and has been associated with increased rates of P. jirovecii infection [48][49][50][51][52][53].…”

Section: Introductionmentioning

confidence: 99%

Deep mutational scanning ofPneumocystis jiroveciidihydrofolate reductase reveals allosteric mechanism of resistance to an antifolate

Rouleau,

Dubé,

Gagnon-Arsenault

et al. 2023

Preprint

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Pneumocystis jiroveciiis a fungal pathogen that causes pneumocystis pneumonia, a disease that mainly affects immunocompromised individuals. This fungus has historically been hard to study because of our inability to grow itin vitro. One of the main drug targets inP. jiroveciiis its dihydrofolate reductase (PjDHFR). Here, by using functional complementation of the baker’s yeast ortholog, we show that PjDHFR can be inhibited by the antifolate methotrexate in a dose-dependent manner. Using deep mutational scanning of PjDHFR, we identify mutations conferring resistance to methotrexate. Thirty-one sites spanning the protein have at least one mutation that leads to resistance, for a total of 355 high-confidence resistance mutations. Most resistance-inducing mutations are found inside the active site, and many are structurally equivalent to mutations known to lead to resistance to different antifolates in other organisms. Some sites show specific resistance mutations, where only a single substitution confers resistance, whereas others are more permissive, as several substitutions at these sites confer resistance. Surprisingly, one of the permissive sites (F199) is without direct contact to either ligand or cofactor, suggesting that it acts through an allosteric mechanism. Modeling changes in binding energy between F199 mutants and drug shows that most mutations destabilize interactions between the protein and the drug. This evidence points towards a more important role of this position in resistance than previously estimated and highlights potential unknown allosteric mechanisms of resistance to antifolate in DHFRs. Our results offer unprecedented resources for the interpretation of mutation effects in the main drug target of an uncultivable fungal pathogen.

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The chemotherapeutic drug methotrexate selects for antibiotic resistance

Cited by 2 publications

References 32 publications

Antimicrobial effects, and selection for AMR by non-antibiotic drugs on bacterial communities

Antimicrobial effects, and selection for AMR by non-antibiotic drugs on bacterial communities

Deep mutational scanning ofPneumocystis jiroveciidihydrofolate reductase reveals allosteric mechanism of resistance to an antifolate

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