tRNA Methylation Is a Global Determinant of Bacterial Multi-drug Resistance

Cell Syst. 2019 Apr 24;8(4):302-314.e8. doi: 10.1016/j.cels.2019.03.008. Epub 2019 Apr 10.


Gram-negative bacteria are intrinsically resistant to drugs because of their double-membrane envelope structure that acts as a permeability barrier and as an anchor for efflux pumps. Antibiotics are blocked and expelled from cells and cannot reach high-enough intracellular concentrations to exert a therapeutic effect. Efforts to target one membrane protein at a time have been ineffective. Here, we show that m1G37-tRNA methylation determines the synthesis of a multitude of membrane proteins via its control of translation at proline codons near the start of open reading frames. Decreases in m1G37 levels in Escherichia coli and Salmonella impair membrane structure and sensitize these bacteria to multiple classes of antibiotics, rendering them incapable of developing resistance or persistence. Codon engineering of membrane-associated genes reduces their translational dependence on m1G37 and confers resistance. These findings highlight the potential of tRNA methylation in codon-specific translation to control the development of multi-drug resistance in Gram-negative bacteria.

Keywords: TrmD; drug efflux; m1G37-tRNA; membrane barrier; persistence; proline codons; resistance; tRNAPro.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Anti-Bacterial Agents / pharmacology
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Drug Resistance, Bacterial*
  • Escherichia coli
  • Escherichia coli Proteins / genetics*
  • Escherichia coli Proteins / metabolism
  • Methylation
  • RNA Processing, Post-Transcriptional*
  • RNA, Transfer / genetics
  • RNA, Transfer / metabolism*
  • Salmonella
  • Transcriptome
  • tRNA Methyltransferases / genetics*
  • tRNA Methyltransferases / metabolism


  • Anti-Bacterial Agents
  • Escherichia coli Proteins
  • RNA, Transfer
  • TrmD protein, E coli
  • tRNA Methyltransferases