对头孢地尔的耐药性涉及PER-1β-内酰胺酶的表达以及碳青霉烯耐药菌中铁转运系统的下调。
Resistance to Cefiderocol Involved Expression of PER-1 β-Lactamase and Downregulation of Iron Transporter System in Carbapenem-Resistant .
作者信息
He Yukun, Wang Yifan, Ma Xinqian, Zhao Lili, Guan Jie, Zhao Jin, Yu Wenyi, Li Yanjun, Ni Wentao, Gao Zhancheng
机构信息
Department of Pulmonary and Critical Care Medicine, Peking University People's Hospital, Beijing, People's Republic of China.
Clinical Laboratory, Peking University First Hospital, Beijing, People's Republic of China.
出版信息
Infect Drug Resist. 2022 Dec 7;15:7177-7187. doi: 10.2147/IDR.S392241. eCollection 2022.
BACKGROUND
Cefiderocol (CFDC) is a promising antimicrobial agent against multidrug resistant Gram-negative bacteria. However, CFDC resistance has emerged in carbapenem-resistant (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 BL21 strain to determine the impact of and the combined impact of and 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 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 BL21 carrying the gene increased 64-fold and recombinant BL21 carrying both the and 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 , and , 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 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.
背景
头孢地尔（CFDC）是一种针对多重耐药革兰氏阴性菌的有前景的抗菌剂。然而，耐碳青霉烯类（CR-AB）细菌中已出现对CFDC的耐药性，但其潜在机制仍不清楚。
方法
对CFDC不敏感和CFDC敏感的分离株进行全基因组测序和转录组测序。将两种不同的重组质粒电转化到BL21菌株中，以确定[具体基因]以及[具体基因]和[具体基因]的组合对CFDC耐药性的影响。
结果
对55株CR-AB分离株进行测序，其最低抑菌浓度（MIC）范围为0.06 mg/L至>256 mg/L，包括47株CFDC不敏感和8株CFDC敏感分离株。两株CFDC不敏感分离株属于ST104，其余分离株属于ST2，且[具体基因]仅存在于CFDC不敏感分离株中。在4株CFDC敏感分离株的青霉素结合蛋白（PBPs）中发现了氨基酸替换，MIC略有升高。携带[具体基因]的重组BL21的MIC增加了64倍，携带[具体基因]和[具体基因]的重组BL21的MIC增加了8倍，但两者仍在敏感范围内。对17株CFDC不敏感分离株和8株CFDC敏感分离株的转录组测序显示，在CFDC不敏感分离株中，各种铁转运蛋白如[具体蛋白]、[具体蛋白]和[具体蛋白]以及能量转导系统TonB-ExbB-ExbD的转录水平相对下调。GO富集分析显示，CFDC不敏感分离株中上调的基因主要与氧化还原稳态和应激反应相关。此外，[具体基因]和exbD基因的表达水平与MIC呈负相关。
结论
PER-1的产生、铁转运系统下调和PBPs突变可能协同赋予CR-AB对CFDC的高水平耐药性。
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