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

McLeod, Rima; Muench, Stephen P.; Rafferty, John B.; Kyle, Dennis E.; Mui, Ernest; Kirisits, Michael J.; Mack, Douglas G.; Roberts, Craig W.; Samuel, Benjamin U.; Lyons, Russell E.; Dorris, Mark; Milhous, Wilbur K.; Rice, David W.

doi:10.1016/s0020-7519(01)00111-4

Cited by 183 publications

(151 citation statements)

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“…Rather, most glycerolipids from free T. gondii cells appears to be produced using acyl chains generated by FAS I or FAEs, which are resistant to the FAS II inhibitor thiolactomycin, but sensitive to the general FAS inhibitor cerulenin (5). Together, these analyses highlight the importance [1] of the parasite FAS for bulk acyl lipid syntheses in free stages and [2] of the FAS II activity for the apicoplast biogenesis. Bisanz et al (13) surveyed lipid synthesizing gene candidates in T. gondii, and identified a glycerol-phosphate acyltransferase and a lysophosphatidate acyltransferase (phosphatidic acid synthase) that are predicted to be localized in the apicoplast, supporting the notion that fatty acids produced by FAS II are important for the organelle membrane expansion.…”

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Lipidomic Analysis of Toxoplasma gondii Reveals Unusual Polar Lipids

et al. 2007

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Analysis of the polar lipids of Toxoplasma gondii by electrospray ionization tandem mass spectrometry provides a detailed picture of the lipid molecular species of this parasitic protozoan. Most notably, T. gondii contains a relatively high level, estimated to about 2% of the total polar lipid, of ceramide phosphoethanolamine. The ceramide phosphoethanolamine has a fatty amide profile with only 16-and 18-carbon species. Compared with the host fibroblasts in which it was grown, T. gondii also has higher levels of phosphatidylcholine, but lower levels of sphingomyelin and phosphatidylserine. Analysis at the molecular species level indicated that T. gondii has greater amounts of shorter-chain fatty acid in its polar lipid molecular species than the host fibroblasts. Shorter-chain fatty acids with a combined total of 30 or fewer acyl carbons make up 21% of Toxoplasma's, but only 3% of the host's, diacyl phosphatidylcholine. Furthermore, diacyl phosphatidylcholine with two saturated acyl chains with 12, 14, or 16 carbons make up over 11% of parasite phosphatidylcholine, but less than 3% of the host phosphatidylcholine molecular species. The distinctive T. gondii tachyzoite lipid profile may be particularly suited to the function of parasitic membranes and the interaction of the parasite with the host cell and the host's immune system. Combined with T. gondii genomic data, these lipidomic data will assist in elucidation of metabolic pathways for lipid biosynthesis in this important human pathogen. † This work was supported by NIH NIAID R01s AI27530, AI43228, AI071319, the Research to Prevent Blindness Foundation, and gifts from the Kieweit, Blackmon, Brennan, Koshland, Langel, Morel, Rosenstein, Cussen, Kapnick, and Rooney-Alden families. Work and instrument acquisition at the Kansas Lipidomics Research Center Analytical Laboratory were supported by grants from NSF (MCB 0455318 and DBI 0521587) and NSF's EPSCoR program (EPS-0236913), with matching support from the State of Kansas through Kansas Technology Enterprise Corporation and Kansas State University, as well from NIH grant P20 RR016475 from the INBRE program of the National Center for Research Resources. This is contribution 07-308-J from the Kansas Agricultural Experiment Station.*To whom correspondence should be addressed: Rima McLeod, M.D., The University of Chicago, AMBH S206; 5841 S Maryland Avenue, Chicago, Illinois 60637, Email: rmcleod@midway.uchicago.edu. 1 Abbreviations: ceramide, Cer; ceramide phosphoethanolamine, PE-cer; dihexosylceramide, Dihex-cer; electrospray ionization, ESI; mass spectrometry, MS; phosphatidic acid, PA; phosphatidylcholine, PC; (alkyl or alkenyl)/acyl glycerophosphocholine, ePC; phosphatidylethanolamine, PE; (alkyl or alkenyl)/acyl glycerophosphoethanolamine, ePE; phosphatidylinositol, PI; (alkyl or alkenyl)/ acyl glycerophosphoserine, ePS; Hexosyl ceramide, Hex-cer; phosphatidylserine, PS; sphingomyelin, SM; tandem mass spectrometry, MS/MS. Toxoplasma gondii infects 2-3 billion people throughout the world and is known ...

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Lipidomic Analysis of Toxoplasma gondii Reveals Unusual Polar Lipids

et al. 2007

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“…Enoyl-ACP reductase (ENR) is a key enzyme active in fatty acid synthesis (6). Bacterial and apicomplexan fatty acid synthesis occurs by the type II pathway (6)(7)(8)(9)(10) (Fig.…”

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“…Bacterial and apicomplexan fatty acid synthesis occurs by the type II pathway (6)(7)(8)(9)(10) (Fig. 5, which is published as supporting information on the PNAS web site) and depends on monofunctional polypeptides, including ENR.…”

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“…5, which is published as supporting information on the PNAS web site) and depends on monofunctional polypeptides, including ENR. In contrast, mammalian fatty acid synthesis occurs by the type I pathway in which the key enzymes are present on a polyfunctional single polypeptide (6)(7)(8)(9)(10). In apicomplexans, type II fatty acid synthesis enzymes are in a plastid organelle (6,8).…”

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Delivery of antimicrobials into parasites

Samuel

Hearn

Mack

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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To eliminate apicomplexan parasites, inhibitory compounds must cross host cell, parasitophorous vacuole, and parasite membranes and cyst walls, making delivery challenging. Here, we show that short oligomers of arginine enter Toxoplasma gondii tachyzoites and encysted bradyzoites. Triclosan, which inhibits enoyl-ACP reductase (ENR), conjugated to arginine oligomers enters extracellular tachyzoites, host cells, tachyzoites inside parasitophorous vacuoles within host cells, extracellular bradyzoites, and bradyzoites within cysts. We identify, clone, and sequence T. gondii enr and produce and characterize enzymatically active, recombinant ENR. This enzyme has the requisite amino acids to bind triclosan. Triclosan released after conjugation to octaarginine via a readily hydrolyzable ester linkage inhibits ENR activity, tachyzoites in vitro, and tachyzoites in mice. Delivery of an inhibitor to a microorganism via conjugation to octaarginine provides an approach to transporting antimicrobials and other small molecules to sequestered parasites, a model system to characterize transport across multiple membrane barriers and structures, a widely applicable paradigm for treatment of active and encysted apicomplexan and other infections, and a generic proof of principle for a mechanism of medicine delivery.

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“…Here we focus on one FAS-II enzyme component: enoyl-ACP reductase. Triclosan, a chlorinated bisphenol that is widely used in many contemporary consumer and professional health care products, has been reported to inhibit the in vitro growth of P. falciparum with an IC 50 value of 150-2000 ng ml -1 (McLeod et al 2001). Triclosan has also been shown to offer protection against blood stages of malaria and that the drug target is an enoyl-ACP reductase from P. falciparum (Surolia & Surolia 2001).…”

Section: Validated Targets For Antimalarial Agents Type II Fatty Acidmentioning

confidence: 99%