Crystal Structures of Trimethoprim-Resistant DfrA1 Rationalize Potent Inhibition by Propargyl-Linked Antifolates

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• 作者：Michael N. Lombardo ; Narendran G-Dayanandan ; Dennis L. Wright ; Amy C. Anderson
• 刊名：ACS Infectious Diseases
• 出版年：2016
• 出版时间：February 12, 2016
• 年：2016
• 卷：2
• 期：2
• 页码：149-156
• 全文大小：573K
• ISSN：2373-8227

文摘

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 β-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.