Fatty acid and sterol metabolism: potential antimicrobial targets in apicomplexan and trypanosomatid parasitic protozoa.
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.
Roberts
C W
CW
Department of Immunology, Strathclyde Institute for Biomedical Sciences, University of Strathclyde, Glasgow G4 ONR, Scotland, UK. c.w.roberts@strath.ac.uk
McLeod
R
R
Rice
D W
DW
Ginger
M
M
Chance
M L
ML
Goad
L J
LJ
D000818:Animals; D000890:Anti-Infective Agents / Q000627:therapeutic use*; D064429:Fatty Acid Synthases / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism*; D013261:Sterols / Q000378:metabolism*; D014345:Trypanosoma / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity*
D000890:Anti-Infective Agents; D005227:Fatty Acids; D013261:Sterols; D064429:Fatty Acid Synthases