Methionine-driven methylation modification overcomes plasmid-mediated high-level tigecycline resistance

Dan Fang, Tianqi Xu, Fulei Li, Yue Sun, Jingyi Sun, Yanqing Yin, Haijie Zhang, Zhiqiang Wang () and Yuan Liu ()
Additional contact information
Dan Fang: Yangzhou University
Tianqi Xu: Yangzhou University
Fulei Li: Yangzhou University
Yue Sun: Yangzhou University
Jingyi Sun: Yangzhou University
Yanqing Yin: Yangzhou University
Haijie Zhang: Yangzhou University
Zhiqiang Wang: Yangzhou University
Yuan Liu: Yangzhou University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Tigecycline is a last-resort antibiotic to treat complicated infections caused by multidrug-resistant pathogens, while the emergence of plasmid-mediated tet(X) family severely compromises its clinical efficacy. Novel antimicrobial strategies not limited to new antibiotics in pharmaceutical pipeline are urgently needed. Herein, we reveal the metabolic disparities between tet(X)-negative and -positive E. coli, including distinct energy demand patterns under tigecycline exposure. In particular, the cysteine and methionine metabolism pathway is remarkably downregulated in tet(X)-positive bacteria. More importantly, we find that the addition of exogenous L-methionine (Met) effectively resensitizes tet(X)-positive pathogens to tigecycline. Our mechanistic analysis demonstrates that exogenous Met promotes intracellular tigecycline accumulation by upregulating bacterial proton motive force. Moreover, Met accelerates the conversion to S-adenosyl-L-methionine, an essential methyl donor, thereby enhancing 5mC methylation modification in the promoter region of tet(X4) gene and reducing its expression. Consistently, the potentiation of Met to tigecycline is abolished in tet(X4)-carrying E. coli Δdcm but restored in dcm-complementary bacteria, which encodes DNA-cytosine methyltransferase. In multiple animal models of infection, Met markedly potentiates the effectiveness of tigecycline against pathogenic E. coli and K. pneumoniae. Overall, this work highlights the therapeutic potential of Met in overcoming plasmid-mediated high-level tigecycline resistance, and provides a new paradigm to enhance antibiotic efficacy by harnessing cellular metabolic networks as well as epigenetic modifications.

Date: 2025
References: View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-55791-w Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55791-w

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-55791-w

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().