Our lead peptide, the APIM-peptide, targets DNA sliding clamps. DNA sliding clamps are functionally and structurally conserved in all three domains of life. The bacterial DNA sliding clamp, the β-clamp, is essential for DNA replication and translesion synthesis (TLS). The APIM-peptide binds to the β-clamp and blocks protein interactions important for the execution of these processes. The APIM-peptide efficiently reduces the growth of both gram positive and gram negative bacterial strains as well as biofilm forming and multidrug-resistant bacteria.

We have demonstrated in vivo effects in an MRSA skin infection model and an MRSE bone graft infection model where the APIM-peptide was applied as a gel or in cement, respectively. Importantly, bacteria are killed at doses that are not toxic to human cells, supporting it´s potential for clinical development as an antibiotic. Additionally, the APIM-peptide strongly inhibits mutagenesis, and these anti-mutagenic properties of the APIM-peptide could be important to inhibit the development of antimicrobial resistance when combined with other antibiotics.

We are currently focusing on optimizing the APIM-peptide for increased affinity to the β-clamp, elucidating its mode of action in bacterial stress responses and on selecting a clinical indication for further development of the APIM-peptide as a new “antibiotics”.

Latest publications

1. The bacterial DNA sliding clamp, β-clamp: structure, interactions, dynamics and drug discovery , Cellular and Molecular Life Sciences, May 2024
2. SOS genes are rapidly induced while translesion synthesis polymerase activity is temporally regulated, Frontiers in Microbiology, Mars 2024.
3. Activation of multiple stress responses in Staphylococcus aureus substantially lowers the minimal inhibitory concentration when combining two novel antibiotic drug candidates, Frontiers in Microbiology, September 2023.
4. Survival of Escherichia coli after high-antibiotic stress is dependent on both the pregrown physiological state and incubation conditions, Frontiers in Microbiology, March 2023.
5. Optimized Fast Filtration-Based Sampling and Extraction Enables Precise and Absolute Quantification of the Escherichia coli Central Carbon Metabolome, Metabolites, January 2023
6. Broad-Spectrum Antibacterial Peptide Kills Extracellular and Intracellular Bacteria Without Affecting Epithelialization, Frontiers in Microbiology, November 2021.
7. Nucleoside ANalogues Are Potent Inducers of Pol V-mediated Mutagenesis, Biomolecules, June 2021. 
8. Novel Peptides Targeting the β-Clamp Rapidly Kill Planktonic and Biofilm Staphylococcus epidermidis Both in vitro and in vivo, Frontiers in Microbiology, 17 March 2021
9. Peptides containing the PCNA interacting motif APIM bind to the beta-clamp and inhibit bacterial growth and mutagenesis, Nucleic Acids Research, 04 June 2020

Contact

The project on the APIM-peptide is led by Professor Marit Otterlei

The toxin-antitoxin (TA) systems are widely distributed in bacteria and consist of small genetic elements; a stable toxin and its unstable neutralizing conjugate antitoxin. During stressful conditions, the antitoxin is degraded, leaving free active toxin. Toxins can interfere with essential cellular processes such as DNA replication, translation and cell wall synthesis, and enable bacteria to survive stress by inducing bacterial persistence, biofilm formation and antibiotic tolerance.

However, overexpression of toxins can be lethal to the bacterial cell, and this property can be exploited for antimicrobial purposes. We are currently studying the mode of action and antimicrobial effects of peptides derived from type I TA systems, which interact with the inner membrane and have the potential for development into antimicrobial therapeutics.

Contact

The TA-peptides project is led by Professor Magnar Bjørås

We are screening for small molecule peptide mimickers that have high affinity for the β-clamp/peptide complex in an in silico virtual screen using a crystallized β-clamp protein and about 5 million commercially available compounds and drug-like molecules.

The most potent candidates will be further studied for potential use as antibiotics.

Latest publications

1. Halogenated Pyrrolopyrimidines with Low MIC on Staphylococcus aureus and Synergistic Effects with an Antimicrobial Peptide, Antibiotics, July 2022.
2. Synthesis and Evaluation of Fused Pyrimidines as E. coli Thymidylate Monophosphate Kinase Inhibitors, Chemistry Select, December 2021.

Contact

The project is led by Professor Bård Helge Hoff and Associate Professor Eirik Sundby