The focus of the project titled Targeting antimicrobial resistance (AMR) by inhibition of bacterial stress responses (TAMiR) is to develop antibacterial peptides and small molecules as new antibiotics that can target multidrug resistant bacteria and inhibit antimicrobial resistance.
The TAMiR project is one of the four AMR-related projects funded by the Trond Mohn Foundation (TMS) , and is led by Professor Marit Otterlei. More on the TAMiR project; National Research Programme on Antimicrobial Resistance (TMS)
The TAMiR project is a collaboration between research groups at NTNU, Oslo University Hospital, and the University of Copenhagen, and is branched into research on three different potential new antibiotic drugs.
Research Topics and Publications
Research Topics and Publications
TAMiR research topics and publications
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”.
- Nucleoside ANalogues Are Potent Inducers of Pol V-mediated Mutagenesis, Biomolecules, June 2021.
- 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
- Peptides containing the PCNA interacting motif APIM bind to the beta-clamp and inhibit bacterial growth and mutagenesis, Nucleic Acids Research, 04 June 2020
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.
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.
- I dag - Ekko - NRK Radio, Podcast, P2, NRK radio, August 2022
- Hvorfor utvikles det ikke nye antibiotika? (aftenposten.no), chronicle, Aftenposten, August 2022
- Forskningspodden: Hva skal vi gjøre når antibiotika slutter å fungere? , Podcast-episode i Forskninspodden, July 2022
- Nå skal abonnement på antibiotika testes ut (gemini.no), Podcast «De store spørsmålene», February 2022
- Researchers Night Live 2021 - NTNU, Live Gløshaugen Trondheim, 24.09.2021
- Lovende utvikling av nye antibiotika mot resistente bakterier, oslo-universitetssykehus.no, February 2021.
- Nummer 2 - pest-POSTEN (pestposten.no), magazine for members of Norsk Forening for Infeksjonsmedisinere, 2021
- NRK Radio Ukeslutt, 27.06.2020
- Norske forskere med oppsiktsvekkende oppdagelse – kan ha funnet ny type antibiotika, NRK Trøndelag 24.06.2020
- NRK Radio, Ekko samfunnspodden, 26.03.2019
- Norske forskere med nytt antibiotika-funn, NRK Vestland, 21.02.2019