Discovery of S-MGB-363: a non-covalent DNA minor groove binder that is effective in an ex vivo Aspergillus fumigatus keratitis model

Fungal keratitis (FK) is a devastating corneal infection and a leading cause of fungal-related blindness worldwide, for which new drugs are urgently needed. In this study, we present the discovery of S-MGB-363 , a non-covalent DNA minor groove binder (MGB) from the Strathclyde MGB (S-MGB) class. From a hit identified in a library screen against Aspergillus fumigatus , we synthesised new S-MGBs with broad-spectrum antifungal activity. S-MGB-363 was selected based on potency, selectivity and advantageous fluorescence enabling mechanism of action studies. We demonstrate that S-MGB-363 effectively binds to genomic DNA and explore a potential specific mechanism of uptake in fungi. Finally, we demonstrate S-MGB-363 to be effective in an ex vivo porcine corneal model of A. fumigatus infection, notably resulting in a marked reduction in fungal burden even deep in the corneal tissue.