Antibiotics are used worldwide and are indispensable to treat otherwise uncurable bacterial infections. However, the widespread emergence of bacterial resistance to existing drugs creates a need to develop novel therapeutic agents. The use of short, modified oligonucleotides as inhibitors of bacterial translation seems a promising strategy. Such specifically designed oligonucleotides suppress proper expression of bacterial genes by complementary binding to bacterial DNA or RNA. However, the main and yet unsolved problem precluding their use as antibiotics is that bacteria do NOT uptake oligonucleotides from their environment.

Therefore, the main objectives of the proposal is to find an efficient and a non-invasive way for the delivery of short oligonucleotides to prokaryotic cells. We envisage that conjugation of RNA analogues to vitamin B12 will significantly improve their cellular uptake in bacteria.

The implementation of this research proposal will provide new synthetic methodologies and will give new insights into the delivery of RNA analogues into prokaryotic cells. When the delivery of vitamin B12-oligonucleotide conjugates to bacterial cells is established, we will pave the way for the development of new antibacterials and allow for the delivery of biologicaly active oligonucleotides into prokaryotic cells.

The project involves a novel approach to the delivery of antibacterial oligonucleotide analogues to prokaryotic cells that combines an interdisciplinary expertise, that of a chemist, biophysicist, molecular biologist, and a physician.