Discovery and Development of Novel sliding clamp (DnaN) inhibitors for the treatment of Gram-positive bacterial infections

The global rise of antimicrobial resistance highlights the urgent need for new antibiotics with innovative mechanisms of action. In this regard, the bacterial β-sliding clamp (DnaN), a homodimer of the β subunit of DNA polymerase III essential for processivity in DNA replication and repair, has emerged as a compelling antibacterial target. DnaN is critical for bacterial survival, highly conserved across species, and distinct from its eukaryotic counterpart, making it a prime candidate for the development of broad-spectrum and selective antibacterials. Despite its potential, current DnaN inhibitors, such as Griselimycin, exhibit limited potency and narrow-spectrum activity. To overcome these limitations, our team employed virtual screening techniques, leading to the identification and validation of three promising hit compounds. By modifying the scaffold of hit compound WAM-N17, we successfully optimized its biological properties and established the initial structure-activity relationship (SAR).

Herein, we report the discovery of synthetic small-molecule inhibitors of DnaN, which demonstrate strong binding affinity, functional inhibition of the target, broad-spectrum antibacterial activity, and a favorable in vitro ADMET profile. Supported by a CARB-X-funded hit-to-lead optimization campaign, this novel chemical class has shown significant promise in advancing DnaN-targeted antibacterial therapies.