ABSTRACT
What major challenges remain in this area? As discussed in the previous section, currently there is very litde known in molecular detail about the structure, target recognition and cata lytic activity of the 16S rRNA methyltransferases. Phylogenetic and homology modeling studies should, however, soon be supplemented with high resolution NMR or X-ray crystal structures that can more precisely guide detailed structure-function studies. A methyltransferase-substrate complex structure is likely to pose a major challenge since the majority o f these enzymes are ac tive only against intact 30S subunits and do not bind isolated rRNA fragments. However, with the many advances in high resolution X-ray crystallographic studies o f the ribosome this goal should eventually be achievable. From what is already known, it is unlikely that there will be many great surprises regarding the structure o f the SAM-binding domain and its interaction with the substrate. In any case, due to its high level o f conservation and ubiquity it is unlikely to be a viable target for pharmacological intervention. In contrast, high resolution structure-function studies will be essential to understand the basis o f the specificity these methyltransferases display for their individual targets. Variability in these target recognition domains suggests that it may be feasible to specifically interfere with the activity o f individual resistance enzymes. Such strategies, in combination with appropriate management and development o f current and novel clinical antibiotics, will be essential in order to effectively combat the increasing prevalence and effect of these resistance elements in pathogenic bacteria.
