A trimethoprim derivative impedes antibiotic resistance evolution

Autor: Nicole Poulides, Erdal Toprak, Madhu Sudan Manna, Uttam K. Tambar, Xiaoyu Wang, Da Nae R. Woodard, Ali Rana Atilgan, Yusuf Talha Tamer, John D. Hulleman, Noelle S. Williams, Andrew Y. Koh, Dominika Borek, Ayesha Ahmed, Canan Atilgan, Furkan C.R. Toprak, Ilona K. Gaszek
Rok vydání: 2021
Předmět:
Models
Molecular
0301 basic medicine
Antibiotics
General Physics and Astronomy
Crystallography
X-Ray
medicine.disease_cause
Trimethoprim
0302 clinical medicine
Dihydrofolate reductase
heterocyclic compounds
Escherichia coli Infections
Genetics
Mutation
Multidisciplinary
Antimicrobials
Escherichia coli Proteins
Anti-Bacterial Agents
medicine.drug
Genotype
medicine.drug_class
Science
Biology
Article
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
Antibiotic resistance
parasitic diseases
Escherichia coli
medicine
Humans
Gene
Trimethoprim Resistance
General Chemistry
bacterial infections and mycoses
biology.organism_classification
Tetrahydrofolate Dehydrogenase
030104 developmental biology
Amino Acid Substitution
Genes
Bacterial
Drug Design
biology.protein
Molecular evolution
Folic Acid Antagonists
Directed Molecular Evolution
030217 neurology & neurosurgery
Bacteria
Zdroj: Nature Communications
Nature Communications, Vol 12, Iss 1, Pp 1-10 (2021)
ISSN: 2041-1723
DOI: 10.1038/s41467-021-23191-z
Popis: 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.
The efficacy of the antibiotic trimethoprim, which inhibits bacterial dihydrofolate reductase (DHFR), is limited by the rapid emergence of resistant bacteria. Here, Manna et al. show that 4’-desmethyltrimethoprim inhibits DHFR and a common TMP-resistant variant, and impedes evolution of antibiotic resistance by selecting against the emergence of this variant.
Databáze: OpenAIRE
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