Using sequence-specific oligonucleotides to inhibit bacterial rRNA.

The majority of antibiotics used in the clinic target bacterial protein synthesis. However, the widespread emergence of bacterial resistance to existing drugs creates a need to discover or develop new therapeutic agents. Ribosomal RNA (rRNA) has been a target for numerous antibiotics that bind to functional rRNA regions such as the peptidyl transferase center, polypeptide exit tunnel, and tRNA binding sites. Even though the atomic resolution structures of many ribosome-antibiotic complexes have been solved, improving the ribosome-acting drugs is difficult because the large rRNA has a complicated 3D architecture and is surrounded by numerous proteins. Computational approaches, such as structure-based design, often fail when applied to rRNA binders because electrostatics dominate the interactions and the effect of ions and bridging waters is difficult to account for in the scoring functions. Improving the classical anti-ribosomal agents has not proven particularly successful and has not kept pace with acquired resistance. So one needs to look for other ways to combat the ribosomes, finding either new rRNA targets or totally different compounds. There have been some efforts to design translation inhibitors that act on the basis of the sequence-specific hybridization properties of nucleic acid bases. Indeed oligonucleotides hybridizing with functional regions of rRNA have been shown to inhibit translation. Also, some peptides have been shown to be reasonable inhibitors. In this review we describe these nonconventional approaches to screening for ribosome inhibition and function of particular rRNA regions. We discuss inhibitors against rRNA that may be designed according to nucleotide sequence and higher order structure.