ArticleAntimicrobial agents and chemotherapy2010
Inhibition of antibiotic-resistant Staphylococcus aureus by the broad-spectrum dihydrofolate reductase inhibitor RAB1.
Article in Antimicrobial agents and chemotherapy, 2010. 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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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
18 citing papers in PubMed, 44 citations in OpenAlex.
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- Identification of P218 as a potent inhibitor ofRSC medicinal chemistry · 2021Article
- Mutational analysis confirms the presence of distal inhibitor-selectivity determining residues in B. stearothermophilus dihydrofolate reductase.Archives of biochemistry and biophysics · 2020Article
- Inhibitor design to target a unique feature in the folate pocket of Staphylococcus aureus dihydrofolate reductase.European journal of medicinal chemistry · 2020Article
- Genome-Scale Metabolic Modeling for Unraveling Molecular Mechanisms of High Threat Pathogens.Frontiers in cell and developmental biology · 2020Review
- Identification of novel potential antibiotics against Staphylococcus using structure-based drug screening targeting dihydrofolate reductase.Journal of chemical information and modeling · 2014Article
- Synthesis and biological evaluation of 2,4-diaminopyrimidine-based antifolate drugs against Bacillus anthracis.Molecules (Basel, Switzerland) · 2014Article
- The structure and competitive substrate inhibition of dihydrofolate reductase from Enterococcus faecalis reveal restrictions to cofactor docking.Biochemistry · 2014Article
- Utility of the Biosynthetic Folate Pathway for Targets in Antimicrobial Discovery.Antibiotics (Basel, Switzerland) · 2014Review
- Metabolic network analysis-based identification of antimicrobial drug targets in category A bioterrorism agents.PloS one · 2014Article
- Comparative Study of the Frech Catalyst with Two Conventional Catalysts in the Heck Synthesis of 2,4-Diaminopyrimidine-based Antibiotics.Organic preparations and procedures international · 2013Article
- Structure-activity relationship for enantiomers of potent inhibitors of B. anthracis dihydrofolate reductase.Biochimica et biophysica acta · 2013Article
- Inhibition of bacterial dihydrofolate reductase by 6-alkyl-2,4-diaminopyrimidines.ChemMedChem · 2012Article
- Synthesis and biological activity of substituted 2,4-diaminopyrimidines that inhibit Bacillus anthracis.European journal of medicinal chemistry · 2012Article
- Classifying compound mechanism of action for linking whole cell phenotypes to molecular targets.Journal of molecular recognition : JMR · 2012Article
- Role of glutamate 64 in the activation of the prodrug 5-fluorocytosine by yeast cytosine deaminase.Biochemistry · 2012Article
- Antifolate agents: a patent review (2006 - 2010).Expert opinion on therapeutic patents · 2011Review
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
The bacterial burden on human health is quickly outweighing available therapeutics. Our long-term goal is the development of antimicrobials with the potential for broad-spectrum activity. We previously reported phthalazine-based inhibitors of dihydrofolate reductase (DHFR) with potent activity against Bacillus anthracis, a major component of Project BioShield. The most active molecule, named RAB1, performs well in vitro and, in a cocrystal structure, was found deep within the active site of B. anthracis DHFR. We have now examined the activity of RAB1 against a panel of bacteria relevant to human health and found broad-spectrum applicability, particularly with regard to gram-positive organisms. RAB1 was most effective against Staphylococcus aureus, including methicillin- and vancomycin-resistant (MRSA/VRSA) strains. We have determined the cocrystal structure of the wild-type and trimethoprim-resistant (Phe 98 Tyr) DHFR enzyme from S. aureus with RAB1, and we found that rotational freedom of the acryloyl linker region allows the phthalazine moiety to occupy two conformations. This freedom in placement also allows either enantiomer of RAB1 to bind to S. aureus, in contrast to the specificity of B. anthracis for the S-enantiomer. Additionally, one of the conformations of RAB1 defines a unique surface cavity that increases the strength of interaction with S. aureus. These observations provide insights into the binding capacity of S. aureus DHFR and highlight atypical features critical for future exploitation in drug development.
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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.