Resistance to Cefiderocol Involved Expression of PER-1 β-Lactamase and Downregulation of Iron Transporter System in Carbapenem-Resistant Acinetobacter baumannii
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 Uni...
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| Format: | Article |
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Dove Medical Press
2022-12-01
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| Series: | Infection and Drug Resistance |
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| Online Access: | https://www.dovepress.com/resistance-to-cefiderocol-involved-expression-of-per-1--lactamase-and--peer-reviewed-fulltext-article-IDR |
| _version_ | 1811178495490916352 |
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| author | He Y Wang Y Ma X Zhao L Guan J Zhao J Yu W Li Y Ni W Gao Z |
| author_facet | He Y Wang Y Ma X Zhao L Guan J Zhao J Yu W Li Y Ni W Gao Z |
| author_sort | He Y |
| collection | DOAJ |
| description | 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 wentao.qingdao@163.com; zcgao@bjmu.edu.cnBackground: 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 |
| first_indexed | 2024-04-11T06:19:21Z |
| format | Article |
| id | doaj.art-335a70b99e9c444dbd19a17e109a4309 |
| institution | Directory Open Access Journal |
| issn | 1178-6973 |
| language | English |
| last_indexed | 2024-04-11T06:19:21Z |
| publishDate | 2022-12-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | Infection and Drug Resistance |
| spelling | doaj.art-335a70b99e9c444dbd19a17e109a43092022-12-22T04:40:51ZengDove Medical PressInfection and Drug Resistance1178-69732022-12-01Volume 157177718780153Resistance to Cefiderocol Involved Expression of PER-1 β-Lactamase and Downregulation of Iron Transporter System in Carbapenem-Resistant Acinetobacter baumanniiHe YWang YMa XZhao LGuan JZhao JYu WLi YNi WGao ZYukun 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 wentao.qingdao@163.com; zcgao@bjmu.edu.cnBackground: 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 systemshttps://www.dovepress.com/resistance-to-cefiderocol-involved-expression-of-per-1--lactamase-and--peer-reviewed-fulltext-article-IDRcarbapenem-resistant acinetobacter baumanniicefiderocol resistanceblaper-1iron transporter systems |
| spellingShingle | He Y Wang Y Ma X Zhao L Guan J Zhao J Yu W Li Y Ni W Gao Z Resistance to Cefiderocol Involved Expression of PER-1 β-Lactamase and Downregulation of Iron Transporter System in Carbapenem-Resistant Acinetobacter baumannii Infection and Drug Resistance carbapenem-resistant acinetobacter baumannii cefiderocol resistance blaper-1 iron transporter systems |
| title | Resistance to Cefiderocol Involved Expression of PER-1 β-Lactamase and Downregulation of Iron Transporter System in Carbapenem-Resistant Acinetobacter baumannii |
| title_full | Resistance to Cefiderocol Involved Expression of PER-1 β-Lactamase and Downregulation of Iron Transporter System in Carbapenem-Resistant Acinetobacter baumannii |
| title_fullStr | Resistance to Cefiderocol Involved Expression of PER-1 β-Lactamase and Downregulation of Iron Transporter System in Carbapenem-Resistant Acinetobacter baumannii |
| title_full_unstemmed | Resistance to Cefiderocol Involved Expression of PER-1 β-Lactamase and Downregulation of Iron Transporter System in Carbapenem-Resistant Acinetobacter baumannii |
| title_short | Resistance to Cefiderocol Involved Expression of PER-1 β-Lactamase and Downregulation of Iron Transporter System in Carbapenem-Resistant Acinetobacter baumannii |
| title_sort | resistance to cefiderocol involved expression of per 1 beta lactamase and downregulation of iron transporter system in carbapenem resistant acinetobacter baumannii |
| topic | carbapenem-resistant acinetobacter baumannii cefiderocol resistance blaper-1 iron transporter systems |
| url | https://www.dovepress.com/resistance-to-cefiderocol-involved-expression-of-per-1--lactamase-and--peer-reviewed-fulltext-article-IDR |
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