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

Cite this

McLeod, R., Muench, S. P., Rafferty, J. B., Kyle, D. E., Mui, E. J., Kirisits, M. J., Mack, D. G., Roberts, C. W., Samuel, B. U., Lyons, R. E., Dorris, M., Milhous, W. K., & Rice, D. W. (2001). Triclosan inhibits the growth of Plasmodium falciparum and Toxoplasma gondii by inhibition of apicomplexan Fab I. International Journal for Parasitology, 31(2), 109-113. https://doi.org/10.1016/S0020-7519(01)00111-4