ArticleJournal of the American Chemical Society2015
Nonracemic Antifolates Stereoselectively Recruit Alternate Cofactors and Overcome Resistance in S. aureus.
Article in Journal of the American Chemical Society, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 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.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
19 citing papers in PubMed, 38 citations in OpenAlex.
- Cationic indium catalysis as a powerful tool for generating α-alkyl propargyl cations for SCommunications chemistry · 2023Article
- Folate-mediated one-carbon metabolism as a potential antifungal target for the sustainable cultivation of microalga Haematococcus pluvialis.Biotechnology for biofuels and bioproducts · 2023Article
- Structure-guided functional studies of plasmid-encoded dihydrofolate reductases reveal a common mechanism of trimethoprim resistance in Gram-negative pathogens.Communications biology · 2022Article
- Chiral evasion and stereospecific antifolate resistance in Staphylococcus aureus.PLoS computational biology · 2022Article
- DNA Damage Kills Bacterial Spores and Cells Exposed to 222-Nanometer UV Radiation.Applied and environmental microbiology · 2020Article
- Multitargeting Compounds: A Promising Strategy to Overcome Multi-Drug Resistant Tuberculosis.Molecules (Basel, Switzerland) · 2020Review
- Trimethoprim and other nonclassical antifolates an excellent template for searching modifications of dihydrofolate reductase enzyme inhibitors.The Journal of antibiotics · 2020Review
- Toward Broad Spectrum Dihydrofolate Reductase Inhibitors Targeting Trimethoprim Resistant Enzymes Identified in Clinical Isolates of Methicillin ResistantACS infectious diseases · 2019Article
- Structure-Guided In Vitro to In Vivo Pharmacokinetic Optimization of Propargyl-Linked Antifolates.Drug metabolism and disposition: the biological fate of chemicals · 2019Article
- Characterization of trimethoprim resistantChemical science · 2017Article
- Pharmaceutical analysis of a novel propargyl-linked antifolate antibiotic in the mouse.Journal of chromatography. B, Analytical technologies in the biomedical and life sciences · 2017Article
- Direct Substitution of Arylalkynyl Carbinols Provides Access to Diverse Terminal Acetylene Building Blocks.Organic letters · 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 Propargyl-Linked Antifolates Reveal Mechanisms of Antifolate Resistance and Inhibit Trimethoprim-Resistant MRSA Strains Possessing Clinically Relevant Mutations.Journal of medicinal chemistry · 2016Article
- Charged Nonclassical Antifolates with Activity Against Gram-Positive and Gram-Negative Pathogens.ACS medicinal chemistry letters · 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
- Endless Resistance. Endless Antibiotics?MedChemComm · 2016Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
While antifolates such as Bactrim (trimethoprim-sulfamethoxazole; TMP-SMX) continue to play an important role in treating community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA), resistance-conferring mutations, specifically F98Y of dihydrofolate reductase (DHFR), have arisen and compromise continued use. In an attempt to extend the lifetime of this important class, we have developed a class of propargyl-linked antifolates (PLAs) that exhibit potent inhibition of the enzyme and bacterial strains. Probing the role of the configuration at the single propargylic stereocenter in these inhibitors required us to develop a new approach to nonracemic 3-aryl-1-butyne building blocks by the pairwise use of asymmetric conjugate addition and aldehyde dehydration protocols. Using this new route, a series of nonracemic PLA inhibitors was prepared and shown to possess potent enzyme inhibition (IC50 values <50 nM), antibacterial effects (several with MIC values <1 μg/mL) and to form stable ternary complexes with both wild-type and resistant mutants. Unexpectedly, crystal structures of a pair of individual enantiomers in the wild-type DHFR revealed that the single change in configuration of the stereocenter drove the selection of an alternative NADPH cofactor, with the minor α-anomer appearing with R-27. Remarkably, this cofactor switching becomes much more prevalent when the F98Y mutation is present. The observation of cofactor site plasticity leads to a postulate for the structural basis of TMP resistance in DHFR and also suggests design strategies that can be used to target these resistant enzymes.
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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.