Journal
CELL SYSTEMS
Volume 8, Issue 4, Pages 302-+Publisher
CELL PRESS
DOI: 10.1016/j.cels.2019.03.008
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Funding
- US National Institutes of Health [GM108972, GM114343, GM080279]
- National Science Foundation [DMR-1120901, MCB-1149328]
- Allen Discovery Center at Stanford on Systems Modeling of Infection
- Canadian Institutes of Health Research (CIHR) [MOP-77688]
- JSPS
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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 highenough 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.
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