Novel Inositol Acyltransferase (Gwt1) Inhibitor for Fungal Keratitis Treatment: Evaluation of In Vitro and In Vivo Efficacy and Safety.

Abstract

PURPOSE: Fungal keratitis (FK) is a vision-threatening infection affecting ∼1 million people annually. This study assesses the therapeutic potential of Manogepix (MGX), a first-in-class Gwt1 fungal enzyme inhibitor, using in vitro and in vivo models. METHODS: MGX's in vitro efficacy was evaluated against clinical keratitis isolates of Candida albicans (n = 10), Fusarium solani (n = 8), and Aspergillus flavus (n = 6) by determining minimal inhibitory and fungicidal concentrations (MIC and MFC), biofilm inhibition, morphological changes, time-kill kinetics at MIC and interaction with amphotericin B. Safety was assessed in vitro on human corneal epithelial cells (HCECs) and in vivo via Draize's test. In vivo efficacy was evaluated in a rabbit F. solani keratitis model. Animals received topical MGX (50 µL, 0.01% w/v, 8×/day) for four days, followed by clinical scoring, colony-forming unit (CFU) enumeration, and histopathological analysis. RESULTS: MGX was fungicidal against C. albicans (MIC₉₀: 0.0313, MFC₉₀: 0.156 µg/mL) and fungistatic against F. solani and A. flavus, with IC₈₀ ranges of 0.019-0.312 and 1.25-20 µg/mL, respectively. At MIC and IC80, MGX inhibited biofilm formation, disrupted fungal cellular morphology and proliferation dynamics. MGX exhibited synergistic/additive effects with amphotericin B. MGX was found safe in vitro at 5 µg/mL on HCECs and showed no signs of corneal toxicity in vivo at 100 µg/mL. In the rabbit model F. solani keratitis, MGX treatment reduced the clinical manifestations of FK and significantly reduced CFU counts compared with untreated controls. CONCLUSIONS: MGX demonstrated efficacy against major ocular fungal pathogens and showed a favorable ocular safety profile in both in vitro and in vivo models.