Peptides containing the PCNA interacting motif APIM bind to the β-clamp and inhibit bacterial growth and mutagenesis. Issue 10 (29th April 2020)

• Record Type: Journal Article
• Authors: Nedal, Aina; Ræder, Synnøve B; Dalhus, Bjørn; Helgesen, Emily; Forstrøm, Rune J; Lindland, Kim; Sumabe, Balagra K; Martinsen, Jacob H; Kragelund, Birthe B; Skarstad, Kirsten; Bjørås, Magnar; Otterlei, Marit
• Is Part Of: Nucleic acids research. Volume 48:Issue 10(2020)
• Page Start: 5540
• Page End: 5554
• Publication Date: 2020-04-29
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gkaa278
• Languages: English
• ISSNs: 0305-1048

Abstract

Abstract: In the fight against antimicrobial resistance, the bacterial DNA sliding clamp, β-clamp, is a promising drug target for inhibition of DNA replication and translesion synthesis. The β-clamp and its eukaryotic homolog, PCNA, share a C-terminal hydrophobic pocket where all the DNA polymerases bind. Here we report that cell penetrating peptides containing the PCNA-interacting motif APIM (APIM-peptides) inhibit bacterial growth at low concentrations in vitro, and in vivo in a bacterial skin infection model in mice. Surface plasmon resonance analysis and computer modeling suggest that APIM bind to the hydrophobic pocket on the β-clamp, and accordingly, we find that APIM-peptides inhibit bacterial DNA replication. Interestingly, at sub-lethal concentrations, APIM-peptides have anti-mutagenic activities, and this activity is increased after SOS induction. Our results show that although the sequence homology between the β-clamp and PCNA are modest, the presence of similar polymerase binding pockets in the DNA clamps allows for binding of the eukaryotic binding motif APIM to the bacterial β-clamp. Importantly, because APIM-peptides display both anti-mutagenic and growth inhibitory properties, they may have clinical potential both in combination with other antibiotics and as single agents.