Document Type
Article
Publication Date
4-24-2019
Abstract
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 m 1 G37-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 m 1 G37 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 m 1 G37 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.
Recommended Citation
Masuda, Isao; Matsubara, Ryuma; Christian, Thomas; Rojas, Enrique R.; Yadavalli, Srujana S.; Zhang, Lisheng; Goulian, Mark; Foster, Leonard J.; Huang, Kerwyn Casey; and Hou, Ya-Ming, "tRNA Methylation Is a Global Determinant of Bacterial Multi-drug Resistance." (2019). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 152.
https://jdc.jefferson.edu/bmpfp/152
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
PubMed ID
30981730
Language
English
Comments
This article has been peer reviewed. It is the authors' final version prior to publication in Cell Systems, Volume 8, Issue 4, April 2019, Pages 302-314.e8.
The published version is available at https://doi.org/10.1016/j.cels.2019.03.008. Copyright © Masuda et al.