Publication — IRIC

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

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.

Publication date
November 12, 2020
Principal Investigators
Toulouse JL, Shi G, Lemay-St-Denis C, Ebert MCCJC, Deon D, Gagnon M, Ruediger E, Saint-Jacques K, Forge D, Vanden Eynde JJ, Marinier A, Ji X, Pelletier JN
PubMed reference
ACS Med Chem Lett 2020;11(11):2261-2267
PubMed ID
33214838
Affiliation
Département de biochimie, Université de Montréal, Montréal, Quebec H3T 1J4, Canada.