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

Area of Science:

• Microbiology
• Molecular Biology
• Pharmacology

Background:

• Tigecycline resistance mediated by plasmid-borne tet(X) genes is a growing clinical threat.
• Novel strategies are needed to combat multidrug-resistant pathogens resistant to last-resort antibiotics like tigecycline.

Purpose of the Study:

• To investigate metabolic differences between tigecycline-resistant and -susceptible bacteria.
• To explore L-methionine (Met) as a potential agent to overcome tigecycline resistance.

Main Methods:

• Comparative metabolic profiling of tet(X)-positive and -negative E. coli under tigecycline stress.
• Assessing the effect of exogenous L-methionine on tigecycline efficacy in vitro and in vivo.
• Mechanistic studies involving proton motive force, S-adenosyl-L-methionine levels, and DNA methylation (5mC) of the tet(X4) promoter.

Main Results:

• Cysteine and methionine metabolism were downregulated in tet(X)-positive bacteria.
• Exogenous L-methionine resensitized tet(X)-positive pathogens to tigecycline.
• L-methionine enhanced intracellular tigecycline accumulation and reduced tet(X4) expression by upregulating proton motive force and promoting DNA methylation.

Conclusions:

• L-methionine potentiates tigecycline efficacy against resistant strains by targeting metabolic and epigenetic pathways.
• This approach offers a promising therapeutic strategy to combat tigecycline resistance in infections caused by E. coli and K. pneumoniae.