Resistance to Cefiderocol Involved Expression of PER-1 β-Lactamase and Downregulation of Iron Transporter System in Carbapenem-Resistant Acinetobacter baumannii

Yukun He; Yifan Wang; Xinqian Ma; Lili Zhao; Jie Guan; Jin Zhao; Wenyi Yu; Yanjun Li; Wentao Ni; Zhancheng Gao

doi:10.2147/IDR.S392241

Resistance to Cefiderocol Involved Expression of PER-1 β-Lactamase and Downregulation of Iron Transporter System in Carbapenem-Resistant Acinetobacter baumannii

Infect Drug Resist. 2022 Dec 7:15:7177-7187. doi: 10.2147/IDR.S392241. eCollection 2022.

Authors

Yukun He^#¹, Yifan Wang^#¹, Xinqian Ma¹, Lili Zhao¹, Jie Guan², Jin Zhao³, Wenyi Yu¹, Yanjun Li⁴, Wentao Ni¹, Zhancheng Gao¹

Affiliations

¹ Department of Pulmonary and Critical Care Medicine, Peking University People's Hospital, Beijing, People's Republic of China.
² Clinical Laboratory, Peking University First Hospital, Beijing, People's Republic of China.
³ Department of Respiratory Diseases, Air Force Medical Center, Chinese People's Liberation Army, Beijing, People's Republic of China.
⁴ Clinical Laboratory, The Sixth Medical Center of PLA General Hospital, Beijing, People's Republic of China.

^# Contributed equally.

Abstract

Background: Cefiderocol (CFDC) is a promising antimicrobial agent against multidrug resistant Gram-negative bacteria. However, CFDC resistance has emerged in carbapenem-resistant Acinetobacter baumannii (CR-AB) but the underlying mechanisms remain unclear.

Methods: Whole-genome sequencing and transcriptome sequencing were performed on CFDC-non-susceptible and CFDC-susceptible isolates. Two different recombinant plasmids was electro-transformed into the E. coli BL21 strain to determine the impact of bla_PER and the combined impact of bla_PER-1 and bla_OXA-23 on CFDC resistance.

Results: Fifty-five CR-AB isolates with minimum inhibitory concentrations (MICs) ranged from 0.06 mg/L to >256 mg/L were sequenced, including 47 CFDC-non-susceptible and eight CFDC-susceptible isolates. Two CFDC-non-susceptible isolates belonged to ST104 whereas the remaining isolates belonged to ST2, and bla_PER-1 was present only in CFDC-non-susceptible isolates. Amino acid substitutions were noted in penicillin-binding proteins (PBPs) in four CFDC-susceptible isolates, with slightly elevated MICs. The MICs of recombinant E. coli BL21 carrying the bla_PER-1 gene increased 64-fold and recombinant E. coli BL21 carrying both the bla_PER-1 and bla_OXA-23 genes increased 8-fold but both remained within the susceptibility range. Transcriptome sequencing of 17 CFDC-non-susceptible isolates and eight CFDC-susceptible isolates revealed that transcriptional levels of various iron transport proteins, such as fiu, feoA, and feoB, and the energy transduction system, TonB-ExbB-ExbD, were relatively downregulated in CFDC-non-susceptible isolates. GO enrichment analysis revealed that the upregulated genes in CFDC-non-susceptible isolates were mainly associated with redox homeostasis and stress response. Besides, the expression levels of the bla_OXA-23 and exbD genes were negatively correlated with the MICs.

Conclusion: PER-1 production, iron transport system downregulation, and mutations in PBPs may synergistically impart high-level resistance to CFDC in CR-AB.

Keywords: blaPER-1; carbapenem-resistant Acinetobacter baumannii; cefiderocol resistance; iron transporter systems.

Grants and funding

This work was supported by the National Natural Science Foundation of China (81903672), and Peking University People’s Hospital Research and Development Funds (RS2020-04, RDJP2022-43).