6LC9

Crystal structure of AmpC Ent385 complex form with ceftazidime

Summary for 6LC9

• Entry DOI: 10.2210/pdb6lc9/pdb
• Descriptor: Beta-lactamase, ACYLATED CEFTAZIDIME, GLYCEROL, ... (6 entities in total)
• Functional Keywords: beta-lactamase, class c, ampc, ceftazidime, hydrolase
• Biological source: Enterobacter cloacae
• Total number of polymer chains: 2
• Total formula weight: 80852.24

Authors

Kawai, A.,Doi, Y. (deposition date: 2019-11-18, release date: 2020-04-22, Last modification date: 2024-11-13)

Primary citation

Kawai, A.,McElheny, C.L.,Iovleva, A.,Kline, E.G.,Sluis-Cremer, N.,Shields, R.K.,Doi, Y.
Structural Basis of Reduced Susceptibility to Ceftazidime-Avibactam and Cefiderocol inEnterobacter cloacaeDue to AmpC R2 Loop Deletion.
Antimicrob.Agents Chemother., 64:-, 2020

PubMed Abstract: Ceftazidime-avibactam and cefiderocol are two of the latest generation β-lactam agents that possess expanded activity against highly drug-resistant bacteria, including carbapenem-resistant Here, we show that structural changes in AmpC β-lactamases can confer reduced susceptibility to both agents. A multidrug-resistant clinical strain (Ent385) was found to be resistant to ceftazidime-avibactam and cefiderocol without prior exposure to either agent. The AmpC β-lactamase of Ent385 (AmpC) contained an alanine-proline deletion at positions 294 and 295 (A294_P295del) in the R2 loop. AmpC conferred reduced susceptibility to ceftazidime-avibactam and cefiderocol when cloned into TOP10. Purified AmpC showed increased hydrolysis of ceftazidime and cefiderocol compared to AmpC, in which the deletion was reverted. Comparisons of crystal structures of AmpC and AmpC, the canonical AmpC of complex, revealed that the two-residue deletion in AmpC induced drastic structural changes of the H-9 and H-10 helices and the R2 loop, which accounted for the increased hydrolysis of ceftazidime and cefiderocol. The potential for a single mutation in to confer reduced susceptibility to both ceftazidime-avibactam and cefiderocol requires close monitoring.

PubMed: 32284381
DOI: 10.1128/AAC.00198-20

Experimental method

X-RAY DIFFRACTION (1.65 Å)