5ECX

Klebsiella pneumoniae DfrA1 complexed with NADPH and 6-ethyl-5-(3-(6-(pyridin-4-yl)benzo[d][1,3]dioxol-4-yl)but-1-yn-1-yl)pyrimidine-2,4-diamine

Summary for 5ECX

• Entry DOI: 10.2210/pdb5ecx/pdb
• Related: 5ECC
• Descriptor: Dehydrofolate reductase type I, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 6-ethyl-5-[(3~{S})-3-(6-pyridin-4-yl-1,3-benzodioxol-4-yl)but-1-ynyl]pyrimidine-2,4-diamine, ... (6 entities in total)
• Functional Keywords: antifolates, dfra1, plasmid borne resistance, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Klebsiella pneumoniae
• Total number of polymer chains: 2
• Total formula weight: 37611.85

Authors

Lombardo, M.N.,Anderson, A.C. (deposition date: 2015-10-20, release date: 2016-05-18, Last modification date: 2024-03-06)

Primary citation

Lombardo, M.N.,G-Dayanandan, N.,Wright, D.L.,Anderson, A.C.
Crystal Structures of Trimethoprim-Resistant DfrA1 Rationalize Potent Inhibition by Propargyl-Linked Antifolates.
ACS Infect Dis, 2:149-156, 2016

PubMed Abstract: 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.

PubMed: 27624966
DOI: 10.1021/acsinfecdis.5b00129

Experimental method

X-RAY DIFFRACTION (1.95 Å)