Leveraging Peptaibol Biosynthetic Promiscuity for Next-Generation Antiplasmodial Therapeutics

Malaria remains a worldwide threat,
afflicting over 200 million
people each year. The emergence of drug resistance against existing
therapeutics threatens to destabilize global efforts aimed at controlling Plasmodium spp. parasites, which is expected to leave vast
portions of humanity unprotected against the disease. To address this
need, systematic testing of a fungal natural product extract library
assembled through the University of Oklahoma Citizen Science Soil
Collection Program has generated an initial set of bioactive extracts
that exhibit potent antiplasmodial activity (EC50 <
0.30 μg/mL) and low levels of toxicity against human cells (less
than 50% reduction in HepG2 growth at 25 μg/mL). Analysis of
the two top-performing extracts from Trichoderma sp.
and Hypocrea sp. isolates revealed both contained
chemically diverse assemblages of putative peptaibol-like compounds
that were responsible for their antiplasmodial actions. Purification
and structure determination efforts yielded 30 new peptaibols and
lipopeptaibols (1–14 and 28–43), along with 22 known metabolites (15–27 and 44–52). While several compounds displayed promising activity
profiles, one of the new metabolites, harzianin NPDG I (14), stood out from the others due to its noteworthy potency (EC50 = 0.10 μM against multi-drug-resistant P.
falciparum line Dd2) and absence of gross toxicity toward
HepG2 at the highest concentrations tested (HepG2 EC50 >
25 μM, selectivity index > 250). The unique chemodiversity
afforded
by these fungal isolates serves to unlock new opportunities for translating
peptaibols into a bioactive scaffold worthy of further development.