التفاصيل البيبلوغرافية
| العنوان: |
Mutation in the two-component regulator BaeSR mediates cefiderocol resistance and enhances virulence in Acinetobacter baumannii |
| المؤلفون: |
Liu, Xiaochen, Chang, Yunjie, Xu, Qingye, Zhang, Wang, Huang, Zhen, Zhang, Linyue, Weng, Shanshan, Leptihn, Sebastian, Jiang, Yan, Yu, Yunsong, Hua, Xiaoting |
| المساهمون: |
Cui, Li, MOST | National Natural Science Foundation of China |
| المصدر: |
mSystems ; ISSN 2379-5077 |
| بيانات النشر: |
American Society for Microbiology |
| سنة النشر: |
2023 |
| الوصف: |
Acinetobacter baumannii has become one of the most challenging pathogens in many countries with limited treatment options available. Cefiderocol, a novel siderophore-conjugated cephalosporin, shows potent in vitro activity against A. baumannii , including isolates resistant to carbapenems. To date, few reports on the mechanisms of cefiderocol resistance are available. In order to investigate potential mechanisms of cefiderocol resistance in A. baumannii , we performed in vitro evolution experiments at sub-lethal concentrations of the antibiotic. All four cefiderocol-resistant strains obtained harbored mutations in two-component system BaeS-BaeR. When we engineered the mutations of BaeS (D89V) and BaeR (S104N) into the genome of ATCC 17978, these mutations increased cefiderocol minimum inhibitory concentrations (MICs) by 8-fold to 16-fold. Transcriptome analyses showed that the expression of MacAB-TolC and MFS transporters was up-regulated in BaeSR mutants. Strains over-expressing MFS transporter and MacAB-TolC displayed higher MICs and higher median inhibition concentration (IC 50 ) values, while MICs and IC 50 decreased when efflux pump genes were knocked out. In a BaeR mutant with up-regulated csu operon, we observed a higher number of pili, enhanced surface motility, and increased biofilm formation compared to wild-type ATCC 17978. Using the Galleria mellonella infection model, we found that the BaeS mutant in which paa operon was up-regulated exhibited increased virulence. In conclusion, the mutations in BaeSR decreased cefiderocol susceptibility of A. baumannii through up-regulating efflux pumps gene expression. BaeS or BaeR also controls the expression of csu and paa , influencing biofilm formation, surface motility, and virulence in A. baumannii . IMPORTANCE The widespread prevalence of m ulti- d rug -r esistant A . b aumannii (MDRAB) poses a significant therapeutic challenge. Cefiderocol is considered a promising antibiotic for the treatment of MDRAB infections. Therefore, it is necessary to ... |
| نوع الوثيقة: |
article in journal/newspaper |
| اللغة: |
English |
| DOI: |
10.1128/msystems.01291-22 |
| الإتاحة: |
https://doi.org/10.1128/msystems.01291-22Test |
| حقوق: |
https://creativecommons.org/licenses/by/4.0Test/ ; https://journals.asm.org/non-commercial-tdm-licenseTest |
| رقم الانضمام: |
edsbas.739DEC0A |
| قاعدة البيانات: |
BASE |
