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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2020 |
|---|---|
| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:11 |
|---|---|
| Enthalten in: |
ACS medicinal chemistry letters - 11(2020), 11 vom: 12. Nov., Seite 2261-2267 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Toulouse, Jacynthe L [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
|---|
| Anmerkungen: |
Date Revised 13.11.2021 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
|---|
| doi: |
10.1021/acsmedchemlett.0c00393 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM317819232 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM317819232 | ||
| 003 | DE-627 | ||
| 005 | 20231225164049.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2020 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1021/acsmedchemlett.0c00393 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1059.xml |
| 035 | |a (DE-627)NLM317819232 | ||
| 035 | |a (NLM)33214838 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Toulouse, Jacynthe L |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Dual-Target Inhibitors of the Folate Pathway Inhibit Intrinsically Trimethoprim-Resistant DfrB Dihydrofolate Reductases |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Revised 13.11.2021 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 700 | 1 | |a Shi, Genbin |e verfasserin |4 aut | |
| 700 | 1 | |a Lemay-St-Denis, Claudèle |e verfasserin |4 aut | |
| 700 | 1 | |a Ebert, Maximilian C C J C |e verfasserin |4 aut | |
| 700 | 1 | |a Deon, Daniel |e verfasserin |4 aut | |
| 700 | 1 | |a Gagnon, Marc |e verfasserin |4 aut | |
| 700 | 1 | |a Ruediger, Edward |e verfasserin |4 aut | |
| 700 | 1 | |a Saint-Jacques, Kévin |e verfasserin |4 aut | |
| 700 | 1 | |a Forge, Delphine |e verfasserin |4 aut | |
| 700 | 1 | |a Vanden Eynde, Jean Jacques |e verfasserin |4 aut | |
| 700 | 1 | |a Marinier, Anne |e verfasserin |4 aut | |
| 700 | 1 | |a Ji, Xinhua |e verfasserin |4 aut | |
| 700 | 1 | |a Pelletier, Joelle N |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t ACS medicinal chemistry letters |d 2010 |g 11(2020), 11 vom: 12. Nov., Seite 2261-2267 |w (DE-627)NLM19927455X |x 1948-5875 |7 nnns |
| 773 | 1 | 8 | |g volume:11 |g year:2020 |g number:11 |g day:12 |g month:11 |g pages:2261-2267 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1021/acsmedchemlett.0c00393 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 11 |j 2020 |e 11 |b 12 |c 11 |h 2261-2267 | ||