ArticleAntimicrobial agents and chemotherapy2012
Prospective screening of novel antibacterial inhibitors of dihydrofolate reductase for mutational resistance.
Article in Antimicrobial agents and chemotherapy, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
18 citing papers in PubMed, 30 citations in OpenAlex.
- Exploring the metabolic profile of A. baumannii for antimicrobial development using genome-scale modeling.PLoS pathogens · 2024Article
- Anti-Parasitology · 2023Article
- Resistance to antibacterial antifolates in multidrug-resistant Staphylococcus aureus: prevalence estimates and genetic basis.The Journal of antimicrobial chemotherapy · 2023Article
- Promising Antifungal Molecules against Mucormycosis Agents Identified from Pandemic Response BoxJournal of fungi (Basel, Switzerland) · 2023Article
- Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV Pandemic Response Box.Nature communications · 2021Article
- How quickly can we predict trimethoprim resistance using alchemical free energy methods?Interface focus · 2020Article
- Characteristics of oral methicillin-resistant Staphylococcus epidermidis isolated from dental plaque.International journal of oral science · 2020Article
- OSPREY Predicts Resistance Mutations Using Positive and Negative Computational Protein Design.Methods in molecular biology (Clifton, N.J.) · 2017Article
- MRSA Isolates from United States Hospitals Carry dfrG and dfrK Resistance Genes and Succumb to Propargyl-Linked Antifolates.Cell chemical biology · 2016Article
- Antibacterial Antifolates: From Development through Resistance to the Next Generation.Cold Spring Harbor perspectives in medicine · 2016Review
- Charged Nonclassical Antifolates with Activity Against Gram-Positive and Gram-Negative Pathogens.ACS medicinal chemistry letters · 2016Article
- Charged Propargyl-Linked Antifolates Reveal Mechanisms of Antifolate Resistance and Inhibit Trimethoprim-Resistant MRSA Strains Possessing Clinically Relevant Mutations.Journal of medicinal chemistry · 2016Article
- Crystal Structures of Trimethoprim-Resistant DfrA1 Rationalize Potent Inhibition by Propargyl-Linked Antifolates.ACS infectious diseases · 2016Article
- Propargyl-Linked Antifolates Are Potent Inhibitors of Drug-Sensitive and Drug-Resistant Mycobacterium tuberculosis.PloS one · 2016Article
- Nonracemic Antifolates Stereoselectively Recruit Alternate Cofactors and Overcome Resistance in S. aureus.Journal of the American Chemical Society · 2015Article
- Protein design algorithms predict viable resistance to an experimental antifolate.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- Crystal structures of Klebsiella pneumoniae dihydrofolate reductase bound to propargyl-linked antifolates reveal features for potency and selectivity.Antimicrobial agents and chemotherapy · 2014Article
- Elucidating features that drive the design of selective antifolates using crystal structures of human dihydrofolate reductase.Biochemistry · 2013Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Resistance to trimethoprim (TMP) resulting from point mutations in the enzyme drug target dihydrofolate reductase (DHFR) drives the development of new antifolate inhibitors effective against methicillin-resistant Staphylococcus aureus (MRSA). For the past several years we have used structure-based design to create propargyl-linked antifolates that are highly potent antibacterial agents. In order to focus priority on the development of lead compounds with a low propensity to induce resistance, we prospectively evaluated resistance profiles for two of these inhibitors in an MRSA strain. By selection with the lead inhibitors, we generated resistant strains that contain single point mutations F98Y and H30N associated with TMP resistance and one novel mutation, F98I, in DHFR. Encouragingly, the pyridyl propargyl-linked inhibitor selects mutants at low frequency (6.85 × 10(-10) to 1.65 × 10(-9)) and maintains a low MIC (2.5 μg/ml) and a low mutant prevention concentration (1.25 μg/ml), strongly supporting its position as a lead compound. Results from this prospective screening method inform the continued design of antifolates effective against mutations at the Phe 98 position. Furthermore, the method can be used broadly to incorporate ideas for overcoming resistance early in the development process.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.