Response regulator protein CiaR regulates the transcription of ccn-microRNAs and β-lactam antibiotic resistance conversion of Streptococcus pneumoniae.

Autor: Yang MJ; School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, PR China; The First Hospital of Putian City, Putian Fujian, PR China., Li MJ; School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, PR China., Huang LD; School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, PR China; Yiwu Central Blood Station, Yiwu, Zhejiang, PR China., Zhang XW; The First Affiliated Hospital of Henan University, Kaifeng Henan, PR China., Huang YY; Hangzhou Red Cross Hospital, Hangzhou Zhejiang, PR China., Gou XY; School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, PR China., Chen SN; School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, PR China., Yan J; Zhejiang Provincial Society for Microbiology, Hangzhou, Zhejiang, PR China., Du P; School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, PR China., Sun AH; School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, PR China. Electronic address: aihuasun@126.com.
Jazyk: angličtina
Zdroj: International journal of antimicrobial agents [Int J Antimicrob Agents] 2025 Jan; Vol. 65 (1), pp. 107387. Date of Electronic Publication: 2024 Nov 19.
DOI: 10.1016/j.ijantimicag.2024.107387
Abstrakt: Background: Streptococcus pneumoniae does not produce β-lactamases, and its reduced susceptibility to β-lactam antibiotics is predominantly caused by mutations of penicillin-binding proteins (PBPs). However, mechanisms of non-PBP mutation-related β-lactam antibiotic resistance in pneumococcal strains remain poorly characterized.
Methods: Susceptibility of S. pneumoniae ATCC49619 and its ciaR gene knockout, complemented, or overexpression mutant (ΔciaR, CΔciaR, or ciaR OE ) to penicillin, cefotaxime, and imipenem was detected using an E-test. Levels of pneumococcal ciaR-mRNA, 5 ccn-microRNAs, and 6 pbps-mRNAs were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Recombinant CiaR (rCiaR) binding to the promoters of ccn-microRNA genes was confirmed using electrophoresis mobility shift and chromatin immunoprecipitation assays. Sequence matching between the ccn-microRNAs and pbps-mRNAs was analyzed using IntaRNA software.
Results: S. pneumoniae ATCC49619 was sensitive to the 3 β-lactam antibiotics, but overexpression of CiaR, a response regulator protein in 2-component system, caused the increase of MICs against these antibiotics. The ciaR OE mutant exhibited the significantly increased transcription of ccn-microRNAs but notably decreased transcription of pbps-mRNAs; conversely, the ΔciaR mutant displayed decreased levels of ccn-microRNAs and increasesed transcription of pbps-mRNAs. rCiaR was able to bind to the promoters of all ccn-microRNA genes in vitro and within cells. The 3 antibiotics at 1/8 minimal inhibitory concentrations caused a significant increase in the ciaR-mRNA and ccn-microRNAs. The mRNA-binding seed sequences in the 5 ccn-microRNAs matched all the promoter-containing sequences of pbps-mRNAs.
Conclusions: β-Lactam antibiotics at low concentrations induce non-PBP mutation-related antibiotic resistance conversion of S. pneumoniae by decrease of PBPs through the pathway of CiaR-mediated transcriptional increase of ccn-microRNAs and ccn-microRNA-dependent degradation of pbp-mRNAs.
(Copyright © 2024 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)
Databáze: MEDLINE
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