Infection and Drug Resistance (Dec 2022)

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

  • He Y,
  • Wang Y,
  • Ma X,
  • Zhao L,
  • Guan J,
  • Zhao J,
  • Yu W,
  • Li Y,
  • Ni W,
  • Gao Z

Journal volume & issue
Vol. Volume 15
pp. 7177 – 7187

Abstract

Read online

Yukun He,1,* Yifan Wang,1,* Xinqian Ma,1 Lili Zhao,1 Jie Guan,2 Jin Zhao,3 Wenyi Yu,1 Yanjun Li,4 Wentao Ni,1 Zhancheng Gao1 1Department of Pulmonary and Critical Care Medicine, Peking University People’s Hospital, Beijing, People’s Republic of China; 2Clinical Laboratory, Peking University First Hospital, Beijing, People’s Republic of China; 3Department of Respiratory Diseases, Air Force Medical Center, Chinese People’s Liberation Army, Beijing, People’s Republic of China; 4Clinical Laboratory, The Sixth Medical Center of PLA General Hospital, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wentao Ni; Zhancheng Gao, Department of Pulmonary and Critical Care Medicine, Peking University People’s Hospital, Beijing, People’s Republic of China, Email [email protected]; [email protected]: 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 blaPER and the combined impact of blaPER-1 and blaOXA-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 blaPER-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 blaPER-1 gene increased 64-fold and recombinant E. coli BL21 carrying both the blaPER-1 and blaOXA-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 blaOXA-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: carbapenem-resistant Acinetobacter baumannii, cefiderocol resistance, blaPER-1, iron transporter systems

Keywords