Griseofulvin impairs intraerythrocytic growth of Plasmodium falciparum through ferrochelatase inhibition but lacks activity in an experimental human infection study.
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.
School of Medicine and The Menzies Research Institute, University of Tasmania, Hobart, Tasmania, Australia.
Clare M
CM
Smith
Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia.
Ante
A
Jerkovic
Joint Mass Spectrometry Facility, Research School of Chemistry, The Australian National University, Canberra, Australian Capital Territory, Australia.
Thy Thuc
TT
Truong
The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.
Simon J
SJ
Foote
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
James S
JS
McCarthy
The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.
Brendan J
BJ
McMorran
D000293:Adolescent; D000328:Adult; D000818:Animals; D000935:Antifungal Agents / Q000378:metabolism / Q000627:therapeutic use*; D016022:Case-Control Studies; D015331:Cohort Studies; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology*; D005260:Female; D005294:Ferrochelatase / Q000037:antagonists & inhibitors*; D005500:Follow-Up Studies; D006118:Griseofulvin / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D010963:Plasmodium falciparum / Q000187:drug effects / Q000254:growth & development*; D011379:Prognosis; D055815:Young Adult
D000935:Antifungal Agents; D006118:Griseofulvin; D005294:Ferrochelatase