5FAQ

OXA-48 in complex with FPI-1465

Summary for 5FAQ

• Entry DOI: 10.2210/pdb5faq/pdb
• Related: 5FA7 5FAO 5FAP 5FAS 5FAT
• Descriptor: Beta-lactamase, CADMIUM ION, CHLORIDE ION, ... (6 entities in total)
• Functional Keywords: hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Klebsiella pneumoniae
• Total number of polymer chains: 2
• Total formula weight: 57282.32

Authors

King, A.M.,King, D.T.,French, S.,Brouillette, E.,Asli, A.,Alexander, A.N.,Vuckovic, M.,Maiti, S.N.,Parr, T.R.,Brown, E.D.,Malouin, F.,Strynadka, N.C.J.,Wright, G.D. (deposition date: 2015-12-11, release date: 2016-01-20, Last modification date: 2024-10-23)

Primary citation

King, A.M.,King, D.T.,French, S.,Brouillette, E.,Asli, A.,Alexander, J.A.,Vuckovic, M.,Maiti, S.N.,Parr, T.R.,Brown, E.D.,Malouin, F.,Strynadka, N.C.,Wright, G.D.
Structural and Kinetic Characterization of Diazabicyclooctanes as Dual Inhibitors of Both Serine-beta-Lactamases and Penicillin-Binding Proteins.
Acs Chem.Biol., 11:864-868, 2016

PubMed Abstract: Avibactam is a diazabicyclooctane β-lactamase inhibitor possessing outstanding but incomplete efficacy against multidrug-resistant Gram-negative pathogens in combination with β-lactam antibiotics. Significant pharmaceutical investment in generating derivatives of avibactam warrants a thorough characterization of their activity. We show here through structural and kinetic analysis that select diazabicyclooctane derivatives display effective but varied inhibition of two clinically important β-lactamases (CTX-M-15 and OXA-48). Furthermore, these derivatives exhibit considerable antimicrobial activity (MIC ≤ 2 μg/mL) against clinical isolates of Pseudomonas aeruginosa, Escherichia coli, and Enterobacter spp. Imaging of cell phenotype along with structural and biochemical experiments unambiguously demonstrate that this activity, in E. coli, is a result of targeting penicillin-binding protein 2. Our results suggest that structure-activity relationship studies for the purpose of drug discovery must consider both β-lactamases and penicillin-binding proteins as targets. We believe that this approach will yield next-generation combination or monotherapies with an expanded spectrum of activity against currently untreatable Gram-negative pathogens.

PubMed: 26731698
DOI: 10.1021/acschembio.5b00944

Experimental method

X-RAY DIFFRACTION (1.96 Å)