Griseofulvin impairs intraerythrocytic growth of Plasmodium falciparum through ferrochelatase inhibition but lacks activity in an experimental human infection study

Abstract

Griseofulvin, an orally active antifungal drug used to treat dermatophyte infections, has a secondary effect of inducing cytochrome P450-mediated production of N-methyl protoporphyrin IX (N-MPP). N-MPP is a potent competitive inhibitor of the heme biosynthetic-enzyme ferrochelatase, and inhibits the growth of cultured erythrocyte stage Plasmodium falciparum. Novel drugs against Plasmodium are needed to achieve malaria elimination. Thus, we investigated whether griseofulvin shows anti-plasmodial activity. We observed that the intraerythrocytic growth of P. falciparum is inhibited in red blood cells pretreated with griseofulvin in vitro. Treatment with 100 μM griseofulvin was sufficient to prevent parasite growth and induce the production of N-MPP. Inclusion of the ferrochelatase substrate PPIX blocked the inhibitory activity of griseofulvin, suggesting that griseofulvin exerts its activity through the N-MPP-dependent inhibition of ferrochelatase. In an ex-vivo study, red blood cells from griseofulvin-treated subjects were refractory to the growth of cultured P. falciparum. However, in a clinical trial griseofulvin failed to show either therapeutic or prophylactic effect in subjects infected with blood stage P. falciparum. Although the development of griseofulvin as an antimalarial is not warranted, it represents a novel inhibitor of P. falciparum growth and acts via the N-MPP-dependent inhibition of ferrochelatase.

TCGA mRNA Expression Analysis of the Heme Biosynthesis Pathway in Diffusely Infiltrating Gliomas: A Comparison of Typically 5-ALA Fluorescent and Non-Fluorescent Gliomas

“…Identification of the exact mechanisms responsible for 5-ALA fluorescence might facilitate the pharmacological modulation of the fluorescence effect in the future. First pharmacological inhibitors of specific heme biosynthesis genes such as N-methylmesoporphyrin and Griseofulvin (both Inhibitors of FECH) have been identified [ 35 , 36 ]. Furthermore, RNA interference (RNAi) offers great potential as a novel therapeutic strategy to specifically and efficiently silence further target genes of the heme biosynthesis pathway [ 37 ].…”

Plasmodium heme biosynthesis: To be or not to be essential?

“…Recent studies reported that P . falciparum parasites showed reduced growth in blood from patients with congenital deficiencies in human ferrochelatase (FECH) or in blood from normal donors treated with the FECH inhibitor N-methylprotoporphyrin (NMPP) [ 17 , 18 ]. From these observations, the authors proposed that blood-stage parasites do require heme biosynthesis by a pathway involving human FECH imported from the host erythrocyte into parasites.…”

Host porphobilinogen deaminase deficiency confers malaria resistance inPlasmodium chabaudibut not inPlasmodium bergheiorPlasmodium falciparumduring intraerythrocytic growth

“…We used the Pbgd MRI58155 mouse line, as well as erythrocytes from AIP patients with PBGD deficiency to investigate potential dependence of Plasmodium on the host enzyme for its growth and survival. These studies were motivated by previous observations that other host heme biosynthetic enzymes are co-opted by the parasite and that they may be potential antimalarial therapeutic targets [5, 9, 11, 15, 19]. We found that P. chabaudi growth was modestly perturbed in mice but not in P. berghei infected mice and human erythrocytes with reduced PBGD levels.…”

“…By virtue of its parasitic lifestyle during the blood-stage of the disease, Plasmodium scavenges erythrocyte enzymes, including protein kinases, cellular redox regulators, and those involved in heme biosynthesis [5–9]. Depriving parasites of such host enzymes may also contribute also to resistance to Plasmodium infection and facilitate identifying novel antimalarial therapeutics as reported in model systems [10, 11].…”