Crystal Structures of Trimethoprim-Resistant DfrA1 Rationalize Potent Inhibition by Propargyl-Linked Antifolates
| Autor: | Narendran G-Dayanandan, Michael N. Lombardo, Dennis L. Wright, Amy C. Anderson |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Klebsiella pneumoniae 030106 microbiology Crystallography X-Ray medicine.disease_cause Trimethoprim beta-Lactamases Article Integrons Microbiology Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Bacterial Proteins Dihydrofolate reductase Escherichia coli medicine Humans chemistry.chemical_classification biology Trimethoprim Resistance biology.organism_classification Enterobacteriaceae Anti-Bacterial Agents Tetrahydrofolate Dehydrogenase 030104 developmental biology Infectious Diseases Enzyme chemistry Antifolate biology.protein Folic Acid Antagonists medicine.drug |
| Zdroj: | ACS Infectious Diseases. 2:149-156 |
| ISSN: | 2373-8227 |
| DOI: | 10.1021/acsinfecdis.5b00129 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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