Resistance to methotrexate due to AcrAB-dependent export from Escherichia coli.
Many laboratory strains of Escherichia coli are resistant to methotrexate (MTX), a folate analogue that binds dihydrofolate reductase (DHFR). Mutations that inactivate either tolC or acrA confer MTX sensitivity. Further, overexpression of a fusion protein with DHFR activity reverses this sensitivity by titrating out intracellular MTX. These results suggest that MTX accumulates in cells where mutations in acrA or tolC have inactivated the TolC-dependent AcrAB multidrug resistance efflux pump.
Kopytek
S J
SJ
Department of Biochemistry and Biophysics and Center for Advanced Biomolecular Research, Texas A&M University, College Station, Texas 77843-2128, USA.
Dyer
J C
JC
Knapp
G S
GS
Hu
J C
JC
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D001692:Biological Transport; D004352:Drug Resistance, Microbial / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D029968:Escherichia coli Proteins; D005493:Folic Acid Antagonists / Q000494:pharmacology; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins; D008727:Methotrexate / Q000494:pharmacology*; D009154:Mutation; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C083497:AcrA protein, E coli; D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D005493:Folic Acid Antagonists; D008074:Lipoproteins; D026901:Membrane Transport Proteins; C073126:tolC protein, E coli; D013762:Tetrahydrofolate Dehydrogenase; D008727:Methotrexate