β-Lactamases (BLs) are important antibiotic-resistance determinants that significantly compromise the efficacy of valuable β-lactam antibacterial drugs. Thus, combinations with BL inhibitor were developed. Avibactam is the first non-β-lactam BL inhibitor introduced into clinical practice. Ceftazidime–avibactam represents one of the few last-resort antibiotics available for the treatment of infections caused by near-pandrug-resistant bacteria. TRU-1 is a chromosomally encoded AmpC-type BL of Aeromonas enteropelogenes, related to the FOX-type BLs and constitutes a good model for class C BLs. TRU-1 crystals provided ultrahigh-resolution diffraction data for the native enzyme and for its complex with avibactam. A comparison of the native and avibactam-bound structures revealed new details in the conformations of residues relevant for substrate and/or inhibitor binding. Furthermore, a comparison of the TRU-1 and Pseudomonas aeruginosa AmpC avibactam-bound structures revealed two inhibitor conformations that were likely to correspond to two different states occurring during inhibitor carbamylation/recyclization.

Pozzi, C., Di Pisa, F., De Luca, F., Benvenuti, M., Docquier, J.D., Mangani, S. (2018). Atomic-Resolution Structure of a Class C β-Lactamase and Its Complex with Avibactam. CHEMMEDCHEM, 13(14), 1437-1446 [10.1002/cmdc.201800213].

Atomic-Resolution Structure of a Class C β-Lactamase and Its Complex with Avibactam

Pozzi, Cecilia;Di Pisa, Flavio;De Luca, Filomena;Benvenuti, Manuela;Docquier, Jean Denis
;
Mangani, Stefano
2018-01-01

Abstract

β-Lactamases (BLs) are important antibiotic-resistance determinants that significantly compromise the efficacy of valuable β-lactam antibacterial drugs. Thus, combinations with BL inhibitor were developed. Avibactam is the first non-β-lactam BL inhibitor introduced into clinical practice. Ceftazidime–avibactam represents one of the few last-resort antibiotics available for the treatment of infections caused by near-pandrug-resistant bacteria. TRU-1 is a chromosomally encoded AmpC-type BL of Aeromonas enteropelogenes, related to the FOX-type BLs and constitutes a good model for class C BLs. TRU-1 crystals provided ultrahigh-resolution diffraction data for the native enzyme and for its complex with avibactam. A comparison of the native and avibactam-bound structures revealed new details in the conformations of residues relevant for substrate and/or inhibitor binding. Furthermore, a comparison of the TRU-1 and Pseudomonas aeruginosa AmpC avibactam-bound structures revealed two inhibitor conformations that were likely to correspond to two different states occurring during inhibitor carbamylation/recyclization.
Pozzi, C., Di Pisa, F., De Luca, F., Benvenuti, M., Docquier, J.D., Mangani, S. (2018). Atomic-Resolution Structure of a Class C β-Lactamase and Its Complex with Avibactam. CHEMMEDCHEM, 13(14), 1437-1446 [10.1002/cmdc.201800213].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/1071875