Metabolism and Resistance of Fusarium spp. to the Manzamine Alkaloids via a Putative Retro Pictet-Spengler Reaction and Utility of the Rational Design of Antimalarial and Antifungal Agents

Abstract

As a part of our continuing investigation of the manzamine alkaloids we studied the in vitro activity of the β-carboline containing manzamine alkaloids against Fusarium solani, Fusarium oxysporium, and Fusarium proliferatum by employing several bioassay techniques including one-dimensional direct bioautography, dilution, and plate susceptibility, and microtiter broth assays. In addition, we also studied the metabolism of the manzamine alkaloids by Fusarium spp. in order to facilitate the redesign of the compounds to prevent resistance of Fusarium spp. through metabolism. The present research reveals that the manzamine alkaloids are inactive against Fusarium spp. and the fungi transform manzamines via hydrolysis, reduction, and a retro Pictet-Spengler reaction. This is the first report to demonstrate an enzymatically retro Pictet-Spengler reaction. The results of this study reveal the utility of the rational design of metabolically stable antifungal agents from this class and the development of manzamine alkaloids as antimalarial drugs through the utilization of Fusarium’s metabolic products to reconstruct the molecule.

The Pictet-Spengler Reaction Updates Its Habits

“…Therefore, a C. globosum IC5I strain was adopted to test for the activation of its "unworking" P-S reaction-based biosynthetic machinery, and 1-methyl-L-tryptophan (1-MT) was demonstrated to be able to up-regulate the FPS expression and condense with the fungal aldehyde flavipin (3,4,5-trihydroxy-6-methylphthalaldehyde) to unexpectedly form a family of skeletally unprecedented alkaloids (Scheme 86), trivially named chaetoglines A-H. Chaetogline B and F have been found to have antibacterial activity comparable to that of tinidazole (a coassayed drug prescribed in clinic for bacterial infections) against pathogenic anaerobes Veillonella parvula, Bacteroides vulgatus, Streptococcus sp., and Peptostreptococcus sp., whereas chaetogline F was also shown to be a potent inhibitor of acetyl-cholinesterase (AChE) [299]. Kasanah and coworkers studied the in vitro activity of the β-carboline-containing manzamine alkaloids against Fusarium solani, Fusarium oxysporum, and Fusarium proliferatum [300]. The data of their bioassays demonstrated that Fusarium spp were resistant to the manzamine alkaloids, because the fungi were able to transform manzamines via hydrolysis, reduction, and a retro-Pictet-Spengler.…”

“…The data of their bioassays demonstrated that Fusarium spp were resistant to the manzamine alkaloids, because the fungi were able to transform manzamines via hydrolysis, reduction, and a retro-Pictet-Spengler. A pathway that involves the reverse catalytic ring opening and the hydrolysis of the iminium Kasanah and coworkers studied the in vitro activity of the β-carboline-containing manzamine alkaloids against Fusarium solani, Fusarium oxysporum, and Fusarium proliferatum [300]. The data of their bioassays demonstrated that Fusarium spp were resistant to the manzamine alkaloids, because the fungi were able to transform manzamines via hydrolysis, reduction, and a retro-Pictet-Spengler.…”