Fatty acid and sterol metabolism: potential antimicrobial targets in apicomplexan and trypanosomatid parasitic protozoa

C W Roberts, R McLeod, D W Rice, M Ginger, M L Chance, L J Goad

Research output: Contribution to journalArticle

205 Citations (Scopus)

Abstract

Current treatments for diseases caused by apicomplexan and trypanosomatid parasites are inadequate due to toxicity, the development of drug resistance and an inability to eliminate all life cycle stages of these parasites from the host. New therapeutics agents are urgently required. It has recently been demonstrated that type II fatty acid biosynthesis occurs in the plastid of Plasmodium falciparum and Toxoplasma gondii and inhibitors of this pathway such as triclosan and thiolactomycin restrict their growth. Furthermore, Trypanosoma brucei has recently been demonstrated to use type II fatty acid biosynthesis for myristate synthesis and to be susceptible to thiolactomycin. As this pathway is absent from mammals, it may provide an excellent target for novel antimicrobial agents to combat these diverse parasites. Leishmania and Trypanosoma parasites produce ergosterol-related sterols by a biosynthetic pathway similar to that operating in pathogenic fungi and their growth is susceptible to sterol biosynthesis inhibitors. Thus, inhibition of squalene 2,3-epoxidase by terbinafine, 14alpha-methylsterol 14-demethylase by azole and triazole compounds and delta(24)-sterol methyl transferase by azasterols all cause a depletion of normal sterols and an accumulation of abnormal amounts of sterol precursors with cytostatic or cytoxic consequences. However, Leishmania parasites can survive with greatly altered sterol profiles induced by continuous treatment with low concentrations of some inhibitors and they also have some ability to utilise and metabolise host sterol. These properties may permit the parasites to evade treatment with sterol biosynthesis inhibitors in some clinical situations and need to be taken into account in the design of future drugs.

LanguageEnglish
Pages129-142
Number of pages14
JournalMolecular and Biochemical Parasitology
Volume126
Issue number2
Early online date11 Dec 2002
DOIs
Publication statusPublished - Feb 2003

Fingerprint

Sterols
Fatty Acids
Parasites
terbinafine
Leishmania
Triclosan
Squalene
Trypanosoma
Ergosterol
Azoles
Trypanosoma brucei brucei
Plastids
Triazoles
Drug Design
Biosynthetic Pathways
Toxoplasma
Myristic Acid
Cytostatic Agents
Plasmodium falciparum
Growth

Keywords

  • cryptosporidium sp.
  • leishmania sp.
  • plasmodium sp.
  • toxoplasma sp.
  • trypanosoma sp.
  • apicomplexans
  • trypanosomatids
  • fatty acid biosynthesis
  • sterol biosynthesis
  • fatty acid biosynthesis inhibitors
  • sterol biosynthesis inhibitors
  • acetyl-coa carboxylase
  • methyl transferbase inhibitors
  • schizotrypanum cruzi epimastigotes
  • ergosterol biosynthesis inhibitors
  • leishmania-mexicana promastigotes
  • in-vitro
  • plasmodium-falciparum
  • toxoplasma-gondii
  • aryloxyphenoxypropionate herbicides
  • ultrastructural alterations

Cite this

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title = "Fatty acid and sterol metabolism: potential antimicrobial targets in apicomplexan and trypanosomatid parasitic protozoa",
abstract = "Current treatments for diseases caused by apicomplexan and trypanosomatid parasites are inadequate due to toxicity, the development of drug resistance and an inability to eliminate all life cycle stages of these parasites from the host. New therapeutics agents are urgently required. It has recently been demonstrated that type II fatty acid biosynthesis occurs in the plastid of Plasmodium falciparum and Toxoplasma gondii and inhibitors of this pathway such as triclosan and thiolactomycin restrict their growth. Furthermore, Trypanosoma brucei has recently been demonstrated to use type II fatty acid biosynthesis for myristate synthesis and to be susceptible to thiolactomycin. As this pathway is absent from mammals, it may provide an excellent target for novel antimicrobial agents to combat these diverse parasites. Leishmania and Trypanosoma parasites produce ergosterol-related sterols by a biosynthetic pathway similar to that operating in pathogenic fungi and their growth is susceptible to sterol biosynthesis inhibitors. Thus, inhibition of squalene 2,3-epoxidase by terbinafine, 14alpha-methylsterol 14-demethylase by azole and triazole compounds and delta(24)-sterol methyl transferase by azasterols all cause a depletion of normal sterols and an accumulation of abnormal amounts of sterol precursors with cytostatic or cytoxic consequences. However, Leishmania parasites can survive with greatly altered sterol profiles induced by continuous treatment with low concentrations of some inhibitors and they also have some ability to utilise and metabolise host sterol. These properties may permit the parasites to evade treatment with sterol biosynthesis inhibitors in some clinical situations and need to be taken into account in the design of future drugs.",
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year = "2003",
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pages = "129--142",
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Fatty acid and sterol metabolism : potential antimicrobial targets in apicomplexan and trypanosomatid parasitic protozoa. / Roberts, C W ; McLeod, R ; Rice, D W ; Ginger, M ; Chance, M L ; Goad, L J .

In: Molecular and Biochemical Parasitology, Vol. 126, No. 2, 02.2003, p. 129-142.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Fatty acid and sterol metabolism

T2 - Molecular and Biochemical Parasitology

AU - Roberts, C W

AU - McLeod, R

AU - Rice, D W

AU - Ginger, M

AU - Chance, M L

AU - Goad, L J

PY - 2003/2

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AB - Current treatments for diseases caused by apicomplexan and trypanosomatid parasites are inadequate due to toxicity, the development of drug resistance and an inability to eliminate all life cycle stages of these parasites from the host. New therapeutics agents are urgently required. It has recently been demonstrated that type II fatty acid biosynthesis occurs in the plastid of Plasmodium falciparum and Toxoplasma gondii and inhibitors of this pathway such as triclosan and thiolactomycin restrict their growth. Furthermore, Trypanosoma brucei has recently been demonstrated to use type II fatty acid biosynthesis for myristate synthesis and to be susceptible to thiolactomycin. As this pathway is absent from mammals, it may provide an excellent target for novel antimicrobial agents to combat these diverse parasites. Leishmania and Trypanosoma parasites produce ergosterol-related sterols by a biosynthetic pathway similar to that operating in pathogenic fungi and their growth is susceptible to sterol biosynthesis inhibitors. Thus, inhibition of squalene 2,3-epoxidase by terbinafine, 14alpha-methylsterol 14-demethylase by azole and triazole compounds and delta(24)-sterol methyl transferase by azasterols all cause a depletion of normal sterols and an accumulation of abnormal amounts of sterol precursors with cytostatic or cytoxic consequences. However, Leishmania parasites can survive with greatly altered sterol profiles induced by continuous treatment with low concentrations of some inhibitors and they also have some ability to utilise and metabolise host sterol. These properties may permit the parasites to evade treatment with sterol biosynthesis inhibitors in some clinical situations and need to be taken into account in the design of future drugs.

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KW - sterol biosynthesis

KW - fatty acid biosynthesis inhibitors

KW - sterol biosynthesis inhibitors

KW - acetyl-coa carboxylase

KW - methyl transferbase inhibitors

KW - schizotrypanum cruzi epimastigotes

KW - ergosterol biosynthesis inhibitors

KW - leishmania-mexicana promastigotes

KW - in-vitro

KW - plasmodium-falciparum

KW - toxoplasma-gondii

KW - aryloxyphenoxypropionate herbicides

KW - ultrastructural alterations

U2 - 10.1016/S0166-6851(02)00280-3

DO - 10.1016/S0166-6851(02)00280-3

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JO - Molecular and Biochemical Parasitology

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