## 3 tRNA Core Modifications and Their Impact on Translation and Stress Adaptation
### tRNA Core Modifications and Their Relation with Stress Adaptation Mechanisms
#### 3.3.4 tRNA Core Modifications in the Response to Antibiotic Stress  
Although tRNA modification genes may be directly involved in bacterial antibiotic resistance--e.g., _trmD_ introducing m\({}^{1}\)G37 in the anticodon loop (reviewed in [167])--, tRNA core modifications have not been shown to confer resistance to antibiotics. However, a recent pioneering study in _Vibrio cholerae_ has uncovered a link between several tRNA modification genes, including those targeting the tRNA core, and the bacterial response to low doses of antibiotics (Table 2) [164]. In this report, initial transposon mutagenesis followed by deep sequencing (TN-seq) [168] in the presence of low-dose antibiotics (sub-minimal inhibitory concentration; sub-MIC) identified several rRNA and tRNA modification genes as important for growth under these antibiotic stress conditions [164]. Several antibiotics were tested, and tRNA modification genes were found to be more largely involved in the response to antibiotics targeting the ribosome, e.g., tobramycin belonging to the amino-glycoside family, than in the response to antibiotics targeting DNA, e.g., ciprofloxacin. These initial genome-wide screens were subsequently complemented with growth competition experiments between the identified tRNA modification deletion strains and the wild-type strain, to determine the effects on the fitness of several antibiotics [164]. Concerning modifications in the tRNA core, under sub-MIC aminoglycoscide treatment, deletion of _truB_ decreased fitness, while deletion of _dusB_ and _trtmH_ conferred a growth advantage. For other antibiotics, such as ciprofloxacin, trimethoprim and carbenicillin, deletion of _dusB_, _truB_, _truB_ and _truH_ were either decreasing or slightly increasing fitness, depending on the antibiotic considered [164]. These diverse phenotypes for a given gene suggest that \begin{table}
\begin{tabular}{c c c c} \hline \hline
**Organism** & **Modification** & **Type of Stress** & **References** \\ \hline _E. coli_, _V. cholerae_ & Gm18 & antibiotics & [123; 164] \\ \hline _S. cerevisiae_ & Gm18 & NaCl & [121] \\ \hline _S. cerevisiae_ & m\({}^{2}_{2}\)G26 & H\({}_{2}\)O\({}_{2}\), MMS, NaAsO\({}_{2}\) & [121; 122] \\ \hline _S. cerevisiae_ & Um44 & H\({}_{2}\)O\({}_{2}\), NaAsO\({}_{2}\), NaOCl & [121; 165] \\ \hline _C. lagenarium_, _P. aeruginosa_, _A. buumannii_, _E. coli_ & m\({}^{7}\)G46 & H\({}_{2}\)O\({}_{2}\) & [160; 161; 162; 158] \\ \hline _T. thermophilus_, _E. coli_ & m\({}^{7}\)G46 & heat & [95; 125] \\ \hline _V. cholerae_ & m\({}^{7}\)G46 & antibiotics & [164] \\ \hline _S. cerevisiae_ & m\({}^{7}\)G46 & MMS, NaAsO\({}_{2}\) & [121; 165] \\ \hline _E. coli_ & acp\({}^{3}\)U47 & heat & [125] \\ \hline _S. cerevisiae_ & m\({}^{5}\)C48/m\({}^{5}\)C50 & amino acid, glucose and uracil starvation & [124] \\ \hline _T. thermophilus_ & m\({}^{5}\)U54 & cold & [107; 108] \\ \hline _P. furious_, _T. thermophilus_ & m\({}^{5}\)S\({}^{2}\)U54 & heat & [95; 104; 107; 166] \\ \hline _T. thermophilus_ & \(\Psi\)55 & cold/heat & [107] \\ \hline _V. cholerae_ & \(\Psi\)55 & antibiotics & [164] \\ \hline _T. thermophilus_ & m\({}^{1}\)A58 & heat & [95; 105; 107] \\ \hline _S. cerevisiae_ & m\({}^{1}\)A58 & H\({}_{2}\)O\({}_{2}\) & [121] \\ \hline _V. cholerae_, _E. coli_ & D & antibiotics & [164] \\ \hline _S. cerevisiae_ & m\({}^{5}\)C & H\({}_{2}\)O\({}_{2}\), MMS, NaAsO\({}_{2}\) & [121] \\ \hline _S. cerevisiae_ & Cm & H\({}_{2}\)O\({}_{2}\), MMS, NaAsO\({}_{2}\) & [121] \\ \hline \hline \end{tabular}
\end{table} 
Table 2: _Cont._the observed effects are not general but antibiotic-specific. Most importantly, this study showed that the effect on fitness in the presence of sub-MIC antibiotics in tRNA modification deletion strains also impacts tolerance to lethal doses of the antibiotics.