Triclosan inhibits the growth of Plasmodium falciparum and Toxoplasma gondii by inhibition of apicomplexan Fab I

R McLeod, S P Muench, J B Rafferty, D E Kyle, E J Mui, M J Kirisits, D G Mack, C W Roberts, B U Samuel, R E Lyons, M Dorris, W K Milhous, D W Rice

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Abstract

Fab I, enoyl acyl carrier protein reductase (ENR), is an enzyme used in fatty acid synthesis. It is a single chain polypeptide in plants, bacteria, and mycobacteria, but is part of a complex polypeptide in animals and fungi. Certain other enzymes in fatty acid synthesis in apicomplexan parasites appear to have multiple forms, homologous to either a plastid, plant-like single chain enzyme or more like the animal complex polypeptide chain. We identified a plant-like Fab I in Plasmodium falciparum and modelled the structure on the Brassica napus and Escherichia coli structures, alone and complexed to triclosan (5-chloro-2-[2,4 dichlorophenoxy] phenol]), which confirmed all the requisite features of an ENR and its interactions with triclosan. Like the remarkable effect of triclosan on a wide variety of bacteria, this compound markedly inhibits growth and survival of the apicomplexan parasites P. falciparum and Toxoplasma gondii at low (i.e. IC50 congruent with150-2000 and 62 ng/ml, respectively) concentrations. Discovery and characterisation of an apicomplexan Fab I and discovery of triclosan as lead compound provide means to rationally design novel inhibitory compounds.
Original languageEnglish
Pages (from-to)109-113
Number of pages5
JournalInternational Journal for Parasitology
Volume31
Issue number2
DOIs
Publication statusPublished - 2001

Keywords

  • amino acid sequence
  • animals
  • antimalarials
  • enoyl-(acyl-carrier-protein) reductase (NADH)
  • enzyme inhibitors
  • humans
  • models, molecular
  • molecular sequence data
  • oxidoreductases
  • plasmodium falciparum
  • sequence alignment
  • toxoplasma
  • triclosan

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