Novel small molecule targeting PgQC reduces Porphyromonas gingivalis virulence

Introduction Periodontitis, a chronic inflammatory disease affecting the periodontium, is primarily driven by dysbiosis of the oral microbiome with Porphyromonas gingivalis as a keystone pathogen. Current therapeutic approaches rely on mechanical debridement and antimicrobials, which face limitations including antibiotic resistance and microbiome disruption. Pathoblockers represent a novel therapeutic strategy that selectively targets virulence factors without bactericidal effects, potentially reducing resistance development while preserving beneficial microbiota. Here, we describe the characterization of S-0636, a novel reversible inhibitor of zinc-dependent glutaminyl cyclase (PgQC), as a compound to selectively inhibit the bacterial virulence of P. gingivalis . Methods The compound's effects were assessed through enzymatic assays, bacterial growth studies, virulence factor activity measurements (gingipain activity, hemagglutination, keratinocyte invasion), selectivity testing against commensal oral bacteria, resistance development analysis over 50 passages, and cytotoxicity evaluation in human cell lines. Results S-0636 demonstrated potent PgQC inhibition with a K i value of 0.014 μM and has successfully reduced the intracellular PgQC activity by 50% at 8 μM and had no bactericidal effects. Treatment of P. gingivalis with S-0636 significantly decreased gingipain activity, impaired hemagglutination capacity, and reduced keratinocyte invasion by 76% at 62.5 μM. The compound showed high selectivity, with no growth inhibition of ten tested oral commensal species at concentrations up to 0.25 mM. Importantly, no resistance development was observed after 50 bacterial passages, and cytotoxicity remained minimal in human cell lines with >80% viability at 0.5 mM. Discussion In previous studies, PgQC was suggested as an enzyme responsible for pGlu-modification and stabilization of bacterial virulence factors. The current study now validates PgQC as an attractive target for pathoblocker development, demonstrating that S-0636 effectively attenuates P. gingivalis pathogenicity through selective virulence factor inhibition while preserving bacterial viability and oral microbiome integrity. The absence of resistance development and low cytotoxicity profile support the potential clinical translation of this approach for periodontal disease management, representing a promising alternative to conventional antimicrobial therapies.