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

Roberts, Craig W.; McLeod, Rima; Rice, David W.; Ginger, Michael L.; Chance, Michaël La; Goad, L. John

doi:10.1016/s0166-6851(02)00280-3

Cited by 270 publications

(256 citation statements)

References 79 publications

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“…In addition, they are effective in inhibiting the growth of several Leishmania spp and Trypanosoma cruzi in vitro. Their proposed action mechanism is the blockade of the parasite cytochrome P450-dependent C14-demethylase (CYP51), which causes the accumulation of 14α-methylsterols and decreases the production of ergostane-derived sterols in fungi and trypanosomatid parasites (Roberts et al 2003). Although most Leishmania spp seem to depend on the de novo sterol biosynthesis, promastigotes of Leishmania donovani, Leishmania braziliensis and Leishmania amazonensis are particularly more sensitive to ketoconazole than Leishmania aethiopica, Leishmania major, Leishmania tropica and Leishmania mexicana (Croft et al 2006).…”

mentioning

confidence: 99%

The stepwise selection for ketoconazole resistance induces upregulation of C14-demethylase (CYP51) in Leishmania amazonensis

Andrade-Neto

Matos-Guedes

Gomes

et al. 2012

Mem. Inst. Oswaldo Cruz

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Ketoconazole is a clinically safe antifungal agent that also inhibits the growth of Leishmania spp. A study was undertaken to determine whether Leishmania parasites are prone to becoming resistant to ketoconazole by upregulating C14-demethylase after stepwise pharmacological pressure. Leishmania amazonensis promastigotes [inhibitory concentration (IC)50 = 2 µM] were subjected to stepwise selection with ketoconazole and two resistant lines were obtained, La8 (IC50 = 8 µM) and La10 (IC50 = 10 µM). As a result, we found that the resistance level was directly proportional to the C14-demethylase mRNA expression level; we also observed that expression levels were six and 12 times higher in La8 and La10, respectively. This is the first demonstration that L. amazonensis can up-regulate C14-demethylase in response to drug pressure and this report contributes to the understanding of the mechanisms of parasite resistance

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mentioning

confidence: 99%

The stepwise selection for ketoconazole resistance induces upregulation of C14-demethylase (CYP51) in Leishmania amazonensis

Andrade-Neto

Matos-Guedes

Gomes

et al. 2012

Mem. Inst. Oswaldo Cruz

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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.…”

mentioning

confidence: 99%

“…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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confidence: 99%

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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“…1b), characterized by hydrophilic polyhydroxyl and hydrophobic polyene aspects. It makes complexes with 24-substituted sterols, such as ergosterol in cell membrane, thus causing pores which alter ion balance and results in cell death (Roberts et al 2003). Leishmania parasites have same sterol (ergosterol) in their cell wall.…”

Section: Amphotericin B and Its Formulationsmentioning

confidence: 99%

“…The lack of concordance is probably due to different assay conditions, already shown to greatly influence antifungal activities, as well as the ability of amastigotes to salvage sterols, such as cholesterol, from host cell macrophages. This factor can reduce the sensitivity of this life cycle stage to azoles (Roberts et al 2003). A number of clinical studies have suggested that these sterol biosynthesis inhibitors are more effective against L. major and L. mexicana infections than against L. donovani or L. braziliensis infections.…”

Section: Azolesmentioning

confidence: 99%

Therapeutic switching in leishmania chemotherapy: a distinct approach towards unsatisfied treatment needs

2011

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Current drugs for the treatment of visceral leishmaniasis are inadequate. No novel compound is in the pipeline. Since economic returns on developing a new drug for neglected disease, leishmaniasis is so low that therapeutic switching represents the only realistic strategy. It refers to ''alternative drug use'' discoveries which differ from the original intent of the drug. Amphotericin B, paromomycin, miltefosine and many other drugs are very successful examples of ''new drugs from old''. This article reviews the discovery, growth and current status of these drugs and concluded that the potential of this approach (therapeutic switching) may use in the development of new antileishmanials in future also.

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

Cited by 270 publications

References 79 publications

The stepwise selection for ketoconazole resistance induces upregulation of C14-demethylase (CYP51) in Leishmania amazonensis

The stepwise selection for ketoconazole resistance induces upregulation of C14-demethylase (CYP51) in Leishmania amazonensis

Delivery of antimicrobials into parasites

Therapeutic switching in leishmania chemotherapy: a distinct approach towards unsatisfied treatment needs

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