Skip NavigationSkip to Content
Return Return to Search Results

Dual-Target Inhibitors of the Folate Pathway Inhibit Intrinsically Trimethoprim-Resistant DfrB Dihydrofolate Reductases

  1. Author:
    Toulouse, Jacynthe L
    Shi,Genbin
    Lemay-St-Denis, Claudèle
    Ebert, Maximilian C C J C
    Deon, Daniel
    Gagnon, Marc
    Ruediger, Edward
    Saint-Jacques, Kévin
    Forge, Delphine
    Vanden Eynde, Jean Jacques
    Marinier, Anne
    Ji,Xinhua
    Pelletier, Joelle N

  2. Author Address

    D 233;partement de biochimie, Universit 233; de Montr 233;al, Montr 233;al, Quebec H3T 1J4, Canada., PROTEO, Quebec G1V 0A6, Canada., CGCC, Center in Green Chemistry and Catalysis, Montr 233;al, Quebec H2V 0B3, Canada., Macromolecular Crystallography Laboratory, NCI, Frederick, Maryland 21702, United States., Chemical Computing Group ULC, Montr 233;al, Quebec H3A 2R7, Canada., Institute for Research in Immunology and Cancer (IRIC), Universit 233; de Montr 233;al, Montr 233;al, Quebec H3T 1J4, Canada., D 233;partement de chimie, Universit 233; de Sherbrooke, Sherbrooke, Quebec J1K 2R1, Canada., Laboratoire de chimie organique, Universit 233; de Mons, 7000 Mons, Belgium.,
    1. Year: 2020
    2. Date: Nov 12
    3. Epub Date: 2020 09 28
  2. Journal: ACS medicinal chemistry letters
    1. 11
    2. 11
    3. Pages: 2261-2267
  4. Type of Article: Article
  5. ISSN: 1948-5875
  1. Abstract:

    Trimethoprim (TMP) is widely used to treat infections in humans and in livestock, accelerating the incidence of TMP resistance. The emergent and largely untracked type II dihydrofolate reductases (DfrBs) are intrinsically TMP-resistant plasmid-borne Dfrs that are structurally and evolutionarily unrelated to chromosomal Dfrs. We report kinetic characterization of the known DfrB family members. Their kinetic constants are conserved and all are poorly inhibited by TMP, consistent with TMP resistance. We investigate their inhibition with known and novel bisubstrate inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK). Importantly, all are inhibited by the HPPK inhibitors, making these molecules dual-target inhibitors of two folate pathway enzymes that are strictly microbial.

    See More

  1. Keywords:

External Sources

  1. View Full Text
  2. DOI: 10.1021/acsmedchemlett.0c00393
  3. PMID: 33214838
  4. PMCID: PMC7667824
  5. View record in Web of Science®
  6. WOS: 000592744800027

Library Notes

  1. Fiscal Year: FY2020-2021
NCI at Frederick

You are leaving a government website.

This external link provides additional information that is consistent with the intended purpose of this site. The government cannot attest to the accuracy of a non-federal site.

Linking to a non-federal site does not constitute an endorsement by this institution or any of its employees of the sponsors or the information and products presented on the site. You will be subject to the destination site's privacy policy when you follow the link.

ContinueCancel