Although only the protein synthesis inhibitors resulted in increased tmRNA expression, a study by Luidalepp et al. (2005) indicated that disruption of trans-translation increased susceptibility to inhibitors of cell wall synthesis as well as to ribosome inhibitors. It was speculated that this reflected an impaired stress response in the trans-translation-deficient organism. However, the lack of a change in tmRNA expression in mycobacteria exposed to cell wall synthesis inhibitors suggested that any

stress response elicited by these agents in mycobacteria did not include trans-translation. The observed changes in tmRNA expression following ribosome inhibition with antimicrobial agents conflict somewhat with the findings of Moore PTC124 purchase & Sauer (2005), who reported that an increased requirement for trans-translation did not increase expression of tmRNA in E. coli. This suggested that bacteria have a significant tmRNA-SmpB reserve capacity. However, there was a key difference between the Moore & Sauer (2005) study and the antimicrobial agents studies presented here and elsewhere (Montero et al., 2006; Paleckova click here et al., 2006). In the Moore & Sauer (2005) study, an increase in trans-translation was directly, and canonically, triggered by overexpression of a transcript lacking a stop codon.

In the other studies, the primary effect of the antimicrobial agents was inhibition Cyclic nucleotide phosphodiesterase of ribosome function, most likely including inhibition of trans-translation. This suggested that the changes in tmRNA expression following exposure to ribosome inhibitors may not have been in response to increased trans-translation. Although ribosome inhibitors, such as erythromycin,

cause ribosome stalling (Rogers et al., 1990; Min et al., 2008), there is evidence that the state of the ribosome is fundamentally different to the stalling associated with triggering of trans-translation. For instance, tRNA is believed to still be able to access the A-site of ribosomes inhibited by agents such as aminoglycosides and macrolides (Walsh, 2003), although the A-site is believed to be vacant when trans-translation is triggered canonically (Moore & Sauer, 2007). Furthermore, there is evidence that translation complexes inhibited by macrolides can dissociate (suggested by the release of peptidyl-tRNA) in the absence of trans-translation (Tenson et al., 2003). Triggering of trans-translation may occur as an indirect effect of drug-associated ribosome dysfunction. For example, aminoglycosides and macrolides can cause translation errors such as frameshifts and stop codon readthrough (Martin et al., 1989; Schroeder et al., 2000; Thompson et al., 2004), which could lead to ribosomes reaching the end of a transcript without encountering a translation termination signal.