5FAT: Oxa-48 In Complex With Fpi-1602

Citation:
Abstract
Avibactam is a diazabicyclooctane beta-lactamase inhibitor possessing outstanding but incomplete efficacy against multidrug-resistant Gram-negative pathogens in combination with beta-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 beta-lactamases (CTX-M-15 and OXA-48). Furthermore, these derivatives exhibit considerable antimicrobial activity (MIC </= 2 mug/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 beta-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.
PDB ID: 5FATDownload
MMDB ID: 135828
PDB Deposition Date: 2015/12/12
Updated in MMDB: 2016/06
Experimental Method:
x-ray diffraction
Resolution: 2.09  Å
Source Organism:
Similar Structures:
Biological Unit for 5FAT: dimeric; determined by author and by software (PISA)
Molecular Components in 5FAT
Label Count Molecule
Proteins (2 molecules)
2
Beta-lactamase
Molecule annotation
Chemicals (13 molecules)
1
2
2
1
3
2
4
8
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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