Discovery of natural CdnP inhibitors through structure-based virtual screening and molecular dynamics simulations

Tuberculosis (TB) remains a leading cause of mortality worldwide, with drug resistance posing a significant challenge to global control efforts. This study represents a major contribution to the field by identifying novel natural product inhibitors targeting CdnP (Rv2837c), a c-di-AMP-specific phosphodiesterase critical for <i>Mycobacterium tuberculosis</i> pathogenesis. The significance of this work lies in its innovative approach to TB therapy by perturbing bacterial nucleotide signaling pathways rather than directly inhibiting bacterial growth. By selectively targeting bacterial CdnP while avoiding host phosphodiesterases, these compounds-particularly ligustroflavone and other flavonoid glucosides-offer a promising foundation for developing host-directed therapeutics with potentially reduced selective pressure for antimicrobial resistance. Furthermore, the detailed structural insights and inhibitory mechanisms elucidated through molecular dynamics simulations provide valuable knowledge for rational drug design. This research bridges natural product discovery with computational biology to address the urgent need for novel TB treatments, especially against drug-resistant strains, presenting a significant advancement toward more effective therapeutic interventions for this persistent global health threat.