|Project Leader: Joanna Trylska, Prof. dr hab.||Project period: 2021 - 2025|
|Project funding: OPUS 19, NCN|
One difficulty in designing new antibiotics is connected with their delivery to bacterial cells. Bacteria protect their cytoplasm with a complex cell envelope, and most antibiotics need to pass
The molecules that we plan to deliver are short oligonucleotides. They will be designed to bind to bacterial RNA observing the Watson-Crick base pairing rules. By such complementary binding, oligonucleotides will block the production of an essential protein and, as a result, inhibit bacterial growth. However, since natural oligonucleotides are unstable, we plan to use a synthetic oligomer called peptide nucleic acid (PNA). PNA oligomers efficiently bind natural RNA, and are not degraded in cells. Unfortunately, bacteria do not take up oligonucleotides, including PNA, from the environment. Thus, our strategy is to design PNA with antibacterial properties and covalently connect it with a siderophore carrier to deliver PNA to bacterial cells. Computer-aided design of the siderophore-like carrier will assure that it is recognized by a siderophore-specific outer-membrane receptor and retrieved to the cytoplasm at the same time “pulling in” the PNA molecule. Importantly, iron metabolism plays crucial roles in bacterial infections; bacteria encounter irondepleted conditions in the host, and need to secrete and take up ferric-siderophores. To our advantage, natural antibiotics, sideromycins, which are composed of a siderophore part connected to the antibiotic, use a similar strategy to pass through the bacterial membrane barrier.
In summary, we will design, synthesize and test siderophore-PNA conjugates composed of a siderophore-analog as a carrier and antibacterial PNA sequence. Our aim is to find a noninvasive way to deliver antibacterial PNA to Gram-negative bacterial cells using bacterial irontransport systems and perform simulations of this transport at atomistic details.
Biomolecular Machines Laboratory