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| == Function == | | == Function == |
| [https://www.uniprot.org/uniprot/A4GRC7_KLEPN A4GRC7_KLEPN] | | [https://www.uniprot.org/uniprot/A4GRC7_KLEPN A4GRC7_KLEPN] |
| <div style="background-color:#fffaf0;">
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| == Publication Abstract from PubMed ==
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| Multidrug-resistant Enterobacteriaceae, notably Escherichia coli and Klebsiella pneumoniae, have become major health concerns worldwide. Resistance to effective therapeutics is often carried by class I and II integrons that can confer insensitivity to carbapenems, extended spectrum beta-lactamases, the antifolate trimethoprim, fluoroquinolones, and aminoglycosides. Specifically of interest to the study here, a prevalent gene (dfrA1) coding for an insensitive dihydrofolate reductase (DHFR) confers 190- or 1000-fold resistance to trimethoprim for K. pneumoniae and E. coli, respectively. Attaining inhibition of both the wild-type and resistant forms of the enzyme is critical for new antifolates. For several years, we have been developing the propargyl-linked antifolates (PLAs) as effective inhibitors against trimethoprim-resistant DHFR enzymes. Here, we show that the PLAs are active against both the wild-type and DfrA1 DHFR proteins. We report two high-resolution crystal structures of DfrA1 bound to potent PLAs. The structure-activity relationships and crystal structures will be critical in driving the design of broadly active inhibitors against wild-type and resistant DHFR.
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| Crystal Structures of Trimethoprim-Resistant DfrA1 Rationalize Potent Inhibition by Propargyl-Linked Antifolates.,Lombardo MN, G-Dayanandan N, Wright DL, Anderson AC ACS Infect Dis. 2016 Feb 12;2(2):149-56. doi: 10.1021/acsinfecdis.5b00129. Epub, 2016 Jan 4. PMID:27624966<ref>PMID:27624966</ref>
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| From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| </div>
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| <div class="pdbe-citations 5ecc" style="background-color:#fffaf0;"></div>
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| ==See Also== | | ==See Also== |
| *[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]] | | *[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]] |
| == References ==
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| <references/>
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| __TOC__ | | __TOC__ |
| </StructureSection> | | </StructureSection> |