Pathogen Enzyme-Mediated Alkoxyamine Homolysis as a Killing Mechanism of <i>Aspergillus fumigatus</i>.

ABSTRACT: The emergence of antifungal-resistant Aspergillus fumigatus (A. fumigatus) became a serious public health concern, underscoring the need for new effective antifungal agents. Here, we present a strategy based on the in situ generation of radical species that are toxic to the pathogen. The synthesis of an alkoxyamine linked to a peptide substrate recognized by A. fumigatus-secreted dipeptidyl peptidase is described. Kinetic experiments show a stable prodrug prior to enzymatic activation. Ensuing peptide cleavage and spontaneous homolysis resulted in the generation of a stable nitroxide and a reactive alkyl radical moiety. Next, the exposure of A. fumigatus spores to the prodrug lead to pathogen growth inhibition in a compound concentration-dependent fashion (e.g., 42% in

SUBMITTER: Filliatre M 

PROVIDER: S-EPMC12299905 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature