Download MendeleyStructural and Kinetic Characterization of Diazabicyclooctanes as Dual Inhibitors of Both Serine-beta-Lactamases and Penicillin-Binding Proteins.
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.(2016) ACS Chem Biol 11: 864-868
- PubMed: 26731698
- DOI: https://doi.org/10.1021/acschembio.5b00944
- Primary Citation of Related Structures:
5FA7, 5FAO, 5FAP, 5FAQ, 5FAS, 5FAT, 5FGZ - 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.
Organizational Affiliation:
M.G. DeGroote Institute for Infectious Disease Research, McMaster University , Hamilton, Ontario L8S 4K1, Canada.
