6XG4

X-ray structure of Escherichia coli dihydrofolate reductase L28R mutant in complex with trimethoprim

Summary for 6XG4

• Entry DOI: 10.2210/pdb6xg4/pdb
• Related: 1dre 1drh 1rh3 7dfr
• Descriptor: Dihydrofolate reductase, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, GLYCEROL, ... (6 entities in total)
• Functional Keywords: dihydrofolate reductase, dhfr, mutant, complex, trimethoprim, oxidoreductase
• Biological source: Escherichia coli
• Total number of polymer chains: 1
• Total formula weight: 20055.55

Authors

Gaszek, I.K.,Manna, M.S.,Borek, D.,Toprak, E. (deposition date: 2020-06-16, release date: 2021-03-24, Last modification date: 2024-04-03)

Primary citation

Manna, M.S.,Tamer, Y.T.,Gaszek, I.,Poulides, N.,Ahmed, A.,Wang, X.,Toprak, F.C.R.,Woodard, D.R.,Koh, A.Y.,Williams, N.S.,Borek, D.,Atilgan, A.R.,Hulleman, J.D.,Atilgan, C.,Tambar, U.,Toprak, E.
A trimethoprim derivative impedes antibiotic resistance evolution.
Nat Commun, 12:2949-2949, 2021

PubMed Abstract: The antibiotic trimethoprim (TMP) is used to treat a variety of Escherichia coli infections, but its efficacy is limited by the rapid emergence of TMP-resistant bacteria. Previous laboratory evolution experiments have identified resistance-conferring mutations in the gene encoding the TMP target, bacterial dihydrofolate reductase (DHFR), in particular mutation L28R. Here, we show that 4'-desmethyltrimethoprim (4'-DTMP) inhibits both DHFR and its L28R variant, and selects against the emergence of TMP-resistant bacteria that carry the L28R mutation in laboratory experiments. Furthermore, antibiotic-sensitive E. coli populations acquire antibiotic resistance at a substantially slower rate when grown in the presence of 4'-DTMP than in the presence of TMP. We find that 4'-DTMP impedes evolution of resistance by selecting against resistant genotypes with the L28R mutation and diverting genetic trajectories to other resistance-conferring DHFR mutations with catalytic deficiencies. Our results demonstrate how a detailed characterization of resistance-conferring mutations in a target enzyme can help identify potential drugs against antibiotic-resistant bacteria, which may ultimately increase long-term efficacy of antimicrobial therapies by modulating evolutionary trajectories that lead to resistance.

PubMed: 34011959
DOI: 10.1038/s41467-021-23191-z

Experimental method

X-RAY DIFFRACTION (2.1 Å)