Macrolides mediate transcriptional activation of the msr(E)-mph(E) operon through histone-like nucleoid-structuring protein (HNS) and cAMP receptor protein (CRP).

Yitao Duan, Shuangqing Liu, Yuting Gao, Peng Zhang, Daqing Mao, Yi Luo

The Journal of antimicrobial chemotherapy 2022 Feb 02

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The msr(E)-mph(E) operon exists widely in diverse species of bacteria and msr(E) and mph(E) genes confer high resistance to macrolides. We aimed to explore whether macrolides regulate the transcription of the operon. Antibiotic resistance genes in clinical isolates of Klebsiella pneumoniae were analysed by WGS. The transcription of the msr(E)-mph(E) operon was investigated by quantitative PCR. Construction of enhanced green fluorescent protein (eGFP) reporter plasmids, gene knockout and complementation experiments were used to further explore the induction mechanism of macrolides for the operon. Sequence analysis was finally used to investigate whether the operon exists widely in diverse species of bacteria. We originally found that the treatment of a pandrug-resistant isolate of K. pneumoniae (KP1517) with macrolides obviously up-regulated the msr(E)-mph(E) operon, which was further confirmed in another nine clinical isolates of K. pneumoniae. The induction mechanism of macrolides for the operon was partly elucidated. Macrolides could activate the operon promoter, and the J10/J35 regions (J10: 5'-AGTTATCAT-3'; J35: 5'-TTGTCT-3') of the promoter were determined. Histone-like nucleoid-structuring protein (HNS) and cAMP receptor protein (CRP) were involved in the erythromycin-mediated activation of the operon promoter. The 476 strains of bacteria carrying the msr(E)-mph(E) operon currently in the NCBI database are mainly Acinetobacter baumannii (158; 33%), K. pneumoniae (95; 20%), Escherichia coli (26; 5%) and Proteus mirabilis (25; 5%). They were mainly isolated from human clinical samples (287; 60%) and had a wide geographical distribution. Macrolides could activate transcription of the msr(E)-mph(E) operon through HNS and CRP in K. pneumoniae and E. coli, and this might occur in diverse species of bacteria. © The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Citation

Yitao Duan, Shuangqing Liu, Yuting Gao, Peng Zhang, Daqing Mao, Yi Luo. Macrolides mediate transcriptional activation of the msr(E)-mph(E) operon through histone-like nucleoid-structuring protein (HNS) and cAMP receptor protein (CRP). The Journal of antimicrobial chemotherapy. 2022 Feb 02;77(2):391-399