Discovery of cyclic peptide natural product inhibitors of Balamuthia mandrillaris

Balamuthia mandrillaris is a pathogenic free-living amoeba that causes infection of central nervous system, called Balamuthia amoebic encephalitis (BAE), as well as cutaneous and systemic diseases. Patients infected with B. mandrillaris have a high mortality rate due to the lack of effective treatments. A combination of non-optimized antimicrobial drug regimen is typically recommended; however, they have poor parasite activity and can cause various severe side effects. Cyclic peptides exhibit a broad spectrum of antimicrobial activities and lower cytotoxicity. In this study, we evaluated the anti-B. mandrillaris effect of cyclic peptides. The predicted natural product-43 (pNP-43), identified from the SNaPP (Synthetic Natural Product Inspired Cyclic Peptides) library, and its derivates displayed a significant inhibition for B. mandrillaris trophozoites. Eight pNPs had IC50s <5 M. Furthermore, all hit pNPs demonstrated minimal hemolytic and cytotoxic effects on human cells. Our study first indicates the anti-B. mandrillaris effect of cyclic peptides, which provides a new direction for drug development. Further studies of the mechanism of action and in vivo effects will be elucidated to confirm the potency as a treatment for B. mandrillaris infection in the future.