Structural Basis of PER-1-Mediated Cefiderocol Resistance and Synergistic Inhibition of PER-1 by Cefiderocol in Combination with Avibactam or Durlobactam in Acinetobacter baumannii

Xiaochen Liu; Tailong Lei; Yunxing Yang; Linghong Zhang; Haiyang Liu; Sebastian Leptihn; Yunsong Yu; Xiaoting Hua

doi:10.1128/aac.00828-22

Structural Basis of PER-1-Mediated Cefiderocol Resistance and Synergistic Inhibition of PER-1 by Cefiderocol in Combination with Avibactam or Durlobactam in Acinetobacter baumannii

Antimicrob Agents Chemother. 2022 Dec 20;66(12):e0082822. doi: 10.1128/aac.00828-22. Epub 2022 Nov 15.

Authors

Xiaochen Liu^#^{1

2

3}, Tailong Lei^#^{1

2

3}, Yunxing Yang^#⁴, Linghong Zhang^{1

2

3}, Haiyang Liu^{1

2

3}, Sebastian Leptihn^{1

5}, Yunsong Yu^{1

2

3}, Xiaoting Hua^{1

2

3

6}

Affiliations

¹ Department of Infectious Diseases, Sir Run Run Shaw Hospitalgrid.415999.9, Zhejiang Universitygrid.13402.34 School of Medicine, Hangzhou, China.
² Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Hangzhou, China.
³ Regional Medical Center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospitalgrid.415999.9, Zhejiang Universitygrid.13402.34 School of Medicine, Hangzhou, China.
⁴ Department of Laboratory Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang Universitygrid.13402.34 School of Medicine, Hangzhou, China.
⁵ Zhejiang Universitygrid.13402.34-University of Edinburgh Institute, Zhejiang University, Haining, China.
⁶ Alibaba-Zhejiang University Joint Research Center of Future Digital Healthcare, Hangzhou, China.

^# Contributed equally.

Abstract

Cefiderocol is a novel siderophore cephalosporin that displays activity against Gram-negative bacteria. To establish cefiderocol susceptibility levels of Acinetobacter baumannii strains from China, we performed susceptibility testing and genomic analyses on 131 clinical isolates. Cefiderocol shows high activity against the strains. The production of PER-1 is the key mechanism of cefiderocol resistance. In silico studies predicted that avibactam and durlobactam could inhibit cefiderocol hydrolysis by PER-1, which was confirmed by determining cefiderocol MICs in combination with inhibitors.

Keywords: Acinetobacter baumannii; PER-1; avibactam; cefiderocol; durlobactam; molecular docking.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acinetobacter baumannii*
Anti-Bacterial Agents* / pharmacology
Cefiderocol
Cephalosporins / pharmacology
Drug Resistance, Multiple, Bacterial / genetics
Gram-Negative Bacteria
Microbial Sensitivity Tests

Substances

Anti-Bacterial Agents
durlobactam
avibactam
Cephalosporins