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Full-Text Articles in Physical Sciences and Mathematics
Biochemical And Structural Analysis Of The Bacterial Enzyme Succinyl-Diaminopimelate Desuccinylase (Dape) From Acinetobacter Baumannii, Emma H. Kelley, George Minasov, Katherine Konczak, Ludmilla Shuvalova, Joseph S. Brunzelle, Shantanu Shukla, Megan Beulke, Teerana Thabthimthong, Ken W. Olsen, Nicole L. Inniss, Karla Jf Satchell, Daniel P. Becker Ph.D.
Biochemical And Structural Analysis Of The Bacterial Enzyme Succinyl-Diaminopimelate Desuccinylase (Dape) From Acinetobacter Baumannii, Emma H. Kelley, George Minasov, Katherine Konczak, Ludmilla Shuvalova, Joseph S. Brunzelle, Shantanu Shukla, Megan Beulke, Teerana Thabthimthong, Ken W. Olsen, Nicole L. Inniss, Karla Jf Satchell, Daniel P. Becker Ph.D.
Chemistry: Faculty Publications and Other Works
There is an urgent need for new antibiotics given the rise of antibiotic resistance, and succinyl-diaminopimelate desuccinylase (DapE, E.C. 3.5.1.18) has emerged as a promising bacterial enzyme target. DapE from Haemophilus influenzae (HiDapE) has been studied and inhibitors identified, but it is essential to explore DapE from different species to assess selective versus broad-spectrum therapeutics. We have determined the structure of DapE from the ESKAPE pathogen Acinetobacter baumannii (AbDapE) and studied inhibition by known inhibitors of HiDapE. AbDapE is inhibited by captopril and sulfate comparable to HiDapE, but AbDapE was not significantly …
Cyclobutanone Inhibitors Of Diaminopimelate Desuccinylase (Dape) As Potential New Antibiotics, Thahani Shifna Habeeb Mohammad, Emma H. Kelley, Cory T. Reidl Dr., Katherine Konczak, Megan Beulke, Janielle Javier, Ken W. Olsen, Daniel P. Becker Ph.D.
Cyclobutanone Inhibitors Of Diaminopimelate Desuccinylase (Dape) As Potential New Antibiotics, Thahani Shifna Habeeb Mohammad, Emma H. Kelley, Cory T. Reidl Dr., Katherine Konczak, Megan Beulke, Janielle Javier, Ken W. Olsen, Daniel P. Becker Ph.D.
Chemistry: Faculty Publications and Other Works
Based on our previous success in using cyclobutanone derivatives as enzyme inhibitors, we have designed and prepared a 37-member library of α-aminocyclobutanone amides and sulfonamides, screened for inhibition of the bacterial enzyme diaminopimelate desuccinylase (DapE), which is a promising antibiotic target, and identified several inhibitors with micromolar inhibitory potency. Molecular docking suggests binding of the deprotonated hydrate of the strained cyclobutanone, and thermal shift analysis with the most potent inhibitor (3y, IC50 = 23.1 µM) enabled determination of a Ki value of 10.2 +/− 0.26 µM and observed two separate Tm values for H. influenzae DapE (HiDapE).