Targeting Bacterial Sliding Clamp for the Treatment of Gram-Positive Bacterial Infections

The persistent rise of antibiotic resistance has created an urgent need for novel anti-infective agents. As current treatments increasingly fail, the search for innovative therapeutic targets becomes more critical. One promising target is DnaN, the bacterial β sliding clamp essential for DNA replication. In our study, structure-based virtual screening identified a hit compound with potent in vitro activity against priority ESKAPE pathogens. Extensive structure–activity relationship (SAR) investigations, supported by structure-based design, were launched to enhance the antibacterial efficacy of frontrunner analogues while optimizing their physicochemical and pharmacokinetic properties. To confirm target engagement, we employed surface plasmon resonance and the antibacterial activity was assessed through minimum inhibitory concentration values against a diverse panel of priority Gram-positive microorganisms. Preliminary results are promising, with frontrunner analogues demonstrating target engagement and achieving antibacterial activities in the low micromolar range (MIC = 2–8 µM). This research suggests that DnaN inhibitors could be transformational anti-infective agents, renewing hope in the battle against resistant bacterial infections and potentially paving the way for effective new treatments.