Targeting Mucoricin: A Novel Approach for Combating Mucormycosis.

During the second wave of the COVID-19 pandemic, mucormycosis cases surged, particularly among individuals with diabetes, causing significant healthcare strain. The high mortality rate is largely due to the severity of the disease and the toxicity of current treatments, which often involve invasive surgery and antifungal therapy. This study focuses on mucoricin, a key virulence factor of , the primary agent of mucormycosis. Mucoricin, a toxin similar to ricin, plays a critical role in disease progression by damaging tissues and evading immune responses. We conducted high-throughput screening of a library of more than a hundred thousand compounds, including known ricin inhibitors, and identified four promising candidates: E860-2820, SB73-0290, N099-0012, and pteroic acid (PTA). PTA showed the most favorable binding free energy (-6.253 kcal/mol) in virtual screening and strong interactions with mucoricin's active site residues, confirmed by surface plasmon resonance. Molecular dynamics simulations validated the stability of the PTA-mucoricin complex. PTA inhibited recombinant mucoricin with an IC(50) of 12.11 μM and protected cells from mucoricin-induced cytotoxicity. These findings highlight PTA as a promising candidate for targeted therapies against mucormycosis.