ACX-801

**ACX-801** is a novel small molecule antibiotic that selectively inhibits the DNA polymerase PolC (DNA polymerase III PolC subunit) in Gram-positive bacteria, adopting a unique non-planar conformation to form base-pairing interactions with DNA in the active site, competing with incoming dGTP nucleotides. Developed through optimization of the ibezapolstat scaffold by researchers at Leiden University Medical Center in collaboration with Acurx Pharmaceuticals, it demonstrates 2- to 4-fold greater potency than ibezapolstat against priority pathogens including vancomycin-resistant *Enterococcus faecium* (VRE), methicillin-resistant *Staphylococcus aureus* (MRSA), and penicillin-resistant *Streptococcus pneumoniae* (PRSP), with MIC values showing activity in the low µg/mL range and no inhibition of Gram-negative *E. coli* or DnaE-type polymerases. Key structural modifications include a (2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl group at R1, hydroxyethyl at R2, and fluoro at R3, enabling improved systemic absorption and pharmacokinetics via oral and intravenous routes in rodents, positioning it as a candidate for treating systemic Gram-positive infections.[1][3][5][11]