A type II pathway for fatty acid biosynthesis presents drug targets in Plasmodium falciparum

被引:160
作者
Waller, RF [1 ]
Ralph, SA
Reed, MB
Su, V
Douglas, JD
Minnikin, DE
Cowman, AF
Besra, GS
McFadden, GI
机构
[1] Univ Melbourne, Sch Biochem & Mol Biol, Melbourne, Vic 3010, Australia
[2] Univ Melbourne, Plant Cell Biol Res Ctr, Sch Bot, Melbourne, Vic 3010, Australia
[3] Walter & Eliza Hall Inst Med Res, Parkville, Vic 3052, Australia
[4] Newcastle Univ, Sch Med, Dept Chem, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England
[5] Newcastle Univ, Sch Med, Dept Microbiol & Immunol, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England
关键词
D O I
10.1128/AAC.47.1.297-301.2003
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
It has long been held that the malaria parasite, Plasmodium sp., is incapable of de novo fatty acid synthesis. This view has recently been overturned with the emergence of data for the presence of a fatty acid biosynthetic pathway in the relict plastid of P. falciparum (known as the apicoplast). This pathway represents the type 11 pathway common to plant chloroplasts and bacteria but distinct from the type I pathway of animals including humans. Specific inhibitors of the type 11 pathway, thiolactomycin and triclosan, have been reported to target this Plasmodium pathway. Here we report further inhibitors of the plastid-based pathway that inhibit Plasmodium parasites. These include several analogues of thiolactomycin, two with sixfold-greater efficacy than thiolactomycin. We also report that parasites respond very rapidly to such inhibitors and that the greatest sensitivity is seen in ring-stage parasites. This study substantiates the importance of fatty acid synthesis for blood-stage parasite survival and shows that this pathway provides scope for the development of novel antimalarial drugs.
引用
收藏
页码:297 / 301
页数:5
相关论文
共 45 条
[1]   THE ORIGINS OF PLASTIDS [J].
CAVALIERSMITH, T .
BIOLOGICAL JOURNAL OF THE LINNEAN SOCIETY, 1982, 17 (03) :289-306
[2]   Antibiotic inhibitors of organellar protein synthesis in Plasmodium falciparum [J].
Clough, B ;
Rangachari, K ;
Strath, M ;
Preiser, PR ;
Wilson, RJMI .
PROTIST, 1999, 150 (02) :189-195
[3]  
CRONAN JE, 1996, ESCHERICHIA COLI SAL, P612
[4]   Tracing the thread of plastid diversity through the tapestry of life [J].
Delwiche, CF .
AMERICAN NATURALIST, 1999, 154 :S164-S177
[5]   QUANTITATIVE ASSESSMENT OF ANTI-MALARIAL ACTIVITY INVITRO BY A SEMIAUTOMATED MICRODILUTION TECHNIQUE [J].
DESJARDINS, RE ;
CANFIELD, CJ ;
HAYNES, JD ;
CHULAY, JD .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1979, 16 (06) :710-718
[6]   IN-VITRO ASSAYS ELUCIDATE PECULIAR KINETICS OF CLINDAMYCIN ACTION AGAINST TOXOPLASMA-GONDII [J].
FICHERA, ME ;
BHOPALE, MK ;
ROOS, DS .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1995, 39 (07) :1530-1537
[7]   A plastid organelle as a drug target in apicomplexan parasites [J].
Fichera, ME ;
Roos, DS .
NATURE, 1997, 390 (6658) :407-409
[8]  
Fish Wallace R., 1995, P133, DOI 10.1016/B978-012473345-9/50009-X
[9]   LIGHT-MICROSCOPE MORPHOLOGY OF PLASMODIUM-FALCIPARUM DURING A SYNCHRONIZED GROWTH-CYCLE INVITRO [J].
FREEMAN, RR ;
HOLDER, AA .
ANNALS OF TROPICAL MEDICINE AND PARASITOLOGY, 1983, 77 (01) :95-96
[10]   Genome sequence of the human malaria parasite Plasmodium falciparum [J].
Gardner, MJ ;
Hall, N ;
Fung, E ;
White, O ;
Berriman, M ;
Hyman, RW ;
Carlton, JM ;
Pain, A ;
Nelson, KE ;
Bowman, S ;
Paulsen, IT ;
James, K ;
Eisen, JA ;
Rutherford, K ;
Salzberg, SL ;
Craig, A ;
Kyes, S ;
Chan, MS ;
Nene, V ;
Shallom, SJ ;
Suh, B ;
Peterson, J ;
Angiuoli, S ;
Pertea, M ;
Allen, J ;
Selengut, J ;
Haft, D ;
Mather, MW ;
Vaidya, AB ;
Martin, DMA ;
Fairlamb, AH ;
Fraunholz, MJ ;
Roos, DS ;
Ralph, SA ;
McFadden, GI ;
Cummings, LM ;
Subramanian, GM ;
Mungall, C ;
Venter, JC ;
Carucci, DJ ;
Hoffman, SL ;
Newbold, C ;
Davis, RW ;
Fraser, CM ;
Barrell, B .
NATURE, 2002, 419 (6906) :498-511