Lead


Lay summary
Identification of ribosomal mechanisms mediating resistance to hygromycin, chloramphenicol and oxazolidinones

Background
The ribosome is target of many important antiinfective agents, including such diverse drugs as aminoglycosides, macrolides and tetracyclines; these compounds interfere with essential steps of protein synthesis, e.g. decoding, proofreading, peptidyl transfer. In spite of decades of use of ribosomal drugs we still do not understand the principles governing selectivity and toxicity of these agents. Understanding the mechanisms of ribosomal resistance at a molecular level is necessary to understand the basis for specificity and selectivity of these antibiotics.

Aim
A detailed understanding of the mechanisms governing resistance towards drugs targeting protein synthesis has long been hampered by the lack of a suitable model organism, due to the fact that rrn resistance mutations in general are recessive and that bacteria harbour several rRNA operons in their chromosome. In this study a single rRNA allelic eubacterial model system is used - besides being amenable to genetic manipulations this model allows the isolation of recessive drug resistance mutations within rrn. In the submitted project it is suggested to isolate and identify ribosomal mutations conferring resistance to drugs targeting bacterial protein synthesis with a view to characterize the mechanisms of action of these drugs and to understand the mechanisms involved in selectivity and toxicity of these agents.

Significance
A better understanding of the mechanisms governing specificity, selectivity and toxicity of antiinfective agents targeting the ribosome is likely to have consequences for future drug design. In principle these studies should contribute to develop new ribosomal antibiotics endowed with less therapeutic toxicity and greater specificity by rational drug design.