Structure-guided functional studies of plasmid-encoded dihydrofolate reductases reveal a common mechanism of trimethoprim resistance in Gram-negative pathogens

Two plasmid-encoded dihydrofolate reductase (DHFR) isoforms, DfrA1 and DfrA5, that give rise to high levels of resistance in Gram-negative bacteria were structurally and biochemically characterized to reveal the mechanism of TMP resistance and to support phylogenic groupings for drug development aga...

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Bibliographic Details
Published in:Communications biology 2022-05, Vol.5 (1), p.459-459, Article 459
Main Authors: Krucinska, Jolanta, Lombardo, Michael N., Erlandsen, Heidi, Estrada, Alexavier, Si, Debjani, Viswanathan, Kishore, Wright, Dennis L.
Format: Article
Language:English
Subjects:
631/154/309/2420
631/535/1266
Antibiotic resistance
Biology
Biomedical and Life Sciences
Catalysis
Dihydrofolate reductase
Drug development
Escherichia coli - genetics
Escherichia coli - metabolism
Folic Acid - analogs & derivatives
Folic Acid Antagonists - chemistry
Folic Acid Antagonists - metabolism
Folic Acid Antagonists - pharmacology
Gram-negative bacteria
Isoforms
Life Sciences
Life Sciences & Biomedicine - Other Topics
Pathogens
Plasmids - genetics
Science & Technology - Other Topics
Tetrahydrofolate Dehydrogenase - chemistry
Tetrahydrofolate Dehydrogenase - genetics
Tetrahydrofolate Dehydrogenase - metabolism
Trimethoprim
Trimethoprim Resistance - genetics
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Summary:Two plasmid-encoded dihydrofolate reductase (DHFR) isoforms, DfrA1 and DfrA5, that give rise to high levels of resistance in Gram-negative bacteria were structurally and biochemically characterized to reveal the mechanism of TMP resistance and to support phylogenic groupings for drug development against antibiotic resistant pathogens. Preliminary screening of novel antifolates revealed related chemotypes that showed high levels of inhibitory potency against Escherichia coli chromosomal DHFR (EcDHFR), DfrA1, and DfrA5. Kinetics and biophysical analysis, coupled with crystal structures of trimethoprim bound to EcDHFR, DfrA1 and DfrA5, and two propargyl-linked antifolates (PLA) complexed with EcDHFR, DfrA1 and DfrA5, were determined to define structural features of the substrate binding pocket and guide synthesis of pan-DHFR inhibitors. Critical residue variations in two of the most clinically prevalent DHFR isoforms are identified as a common structural element in trimethoprim-resistant DHFR which impose changes on enzyme catalysis and ligand-cofactor cooperativity.
ISSN:2399-3642
2399-3642
DOI:10.1038/s42003-022-03384-y