AUTHOR=Ahmed Mohammed M. A. , Tripathi Siddarth K. , Boudreau Paul D. 

TITLE=Comparative metabolomic profiling of Cupriavidus necator B-4383 revealed production of cupriachelin siderophores, one with activity against Cryptococcus neoformans

JOURNAL=Frontiers in Chemistry

VOLUME=11

YEAR=2023

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2023.1256962

DOI=10.3389/fchem.2023.1256962

ISSN=2296-2646

ABSTRACT=<p><italic>Cupriavidus necator</italic> H16 is known to be a rich source of linear lipopeptide siderophores when grown under iron-depleted conditions; prior literature termed these compounds cupriachelins. These small molecules bear <italic>β</italic>-hydroxyaspartate moieties that contribute to a photoreduction of iron when bound as ferric cupriachelin. Here, we present structural assignment of cupriachelins from <italic>C. necator</italic> B-4383 grown under iron limitation. The characterization of B-4383 cupriachelins is based on MS/MS fragmentation analysis, which was confirmed by 1D- and 2D-NMR for the most abundant analog (<bold>1</bold>). The cupriachelin congeners distinguish these two strains with differences in the preferred lipid tail; however, our rigorous metabolomic investigation also revealed minor analogs with changes in the peptide core, hinting at a potential mechanism by which these siderophores may reduce biologically unavailable ferric iron (<bold>4–6</bold>). Antifungal screening of the <italic>C. necator</italic> B-4383 supernatant extract and the isolated cupriachelin analog (<bold>1</bold>) revealed inhibitory activity against <italic>Cryptococcus neoformans</italic>, with IC<sub>50</sub> values of 16.6 and 3.2 μg/mL, respectively. This antifungal activity could be explained by the critical role of the iron acquisition pathway in the growth and pathogenesis of the <italic>C. neoformans</italic> fungal pathogen.</p>