Biochemical alterations in paromomycin-treated Leishmania donovani promastigotes

Maarouf, Mohammad; Lawrence, Françoise; Brown, Spencer C.; Robert-Géro, Malka

doi:10.1007/s004360050232

Cited by 62 publications

(47 citation statements)

References 16 publications

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“…1). The main molecular mechanisms involved in drug resistance are changes in the uptake, qualitative or quantitative modifications of the targets or the enzymatic inactivation of the drug (Maarouf et al 1998). The results presented here demonstrate for the first time that L. amazonensis can diminish its ketoconazole sensitivity mainly by upregulating the expression of C14-demethylase.…”

mentioning

confidence: 52%

“…The induction of resistance and upregulation of the sterol C14-demethylase expression level have also been described in T. cruzi treated with azoles (Buckner et al 1998). However, despite the documented development of resistance to drugs, such as pentavalent antimonials (Ashutosh et al 2007) and paromomycin (Maarouf et al 1998), nothing is reportedly known about the development of an azole resistance for Leishmania (Croft et al 2006).…”

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confidence: 99%

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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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confidence: 52%

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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“…Further studies are needed to define the mechanisms of action drug resistance in Leishmania. Maarouf et al(1998) studied on selected populations of promastigotes demonstrated that resistance was related to decreased drug uptake in L. donovani but due neither to enzymatic modifications nor to any mutation of the small-subunit rRNA gene in L. tropica (Fong et al 1994). Clinically there has been only one report against cutaneous leishmaniasis, suggesting resistance could develop.…”

Section: Paromomycinmentioning

confidence: 99%

“…The leishmanicidal action of paromomycin is likely to be complex (Maarouf et al 1997) L. donovani may be killed through inhibition of parasite metabolism and mitochondrial respiration. In vitro studies have shown that paromomycin can effectively kill both promastigotes and amastigotes (Neal and Croft 1984;Gebre-Hiwot et al 1992;Neal et al 1995).…”

Section: Paromomycinmentioning

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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“…It has been reported that ribosomes are also a target for paromomycin in Leishmania (46). Moreover, it has been suggested that paromomycin generates alterations in membrane composition and fluidity (47) and affects mitochondria (48). Drug-resistant strains have been generated in the laboratory (49), though resistance has not been observed in the field to date, since paromomycin has not been used extensively.…”

Section: Disease and Clinical Manifestationsmentioning

confidence: 99%

Leishmaniasis: Drug resistance and natural products (Review)

Polonio

Efferth²

1998

Int J Mol Med

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Abstract. Epidemics of fatal visceral leishmaniasis caused by the intracellular protozoan Leishmania are a severe public health problem in tropical and subtropical regions of the world. One major drawback in the treatment of leishmaniasis is the emergence of resistance to current chemotherapeutics. Leishmanicidals have to be administered in low doses since commonly used drugs exhibit severe side effects, and hence drug resistance can appear rapidly. Since, to date, vaccination approaches have failed to enter clinical trials, chemotherapy based on small molecules is temporarily the exclusive treatment strategy. There is an urgent need for adding novel drugs with improved features to the pool of current chemotherapeutics. Many compounds derived from natural sources have pharmacological activities and may, thus, be of potential utility in drug development and biomedical research. Natural products, primarily plant-derived substances of diverse structural classes, have been described in the literature showing anti-leishmanial properties. In this review we provide a brief overview of the current treatment and the active principles of established drugs. Furthermore, we focus on the mechanisms of drug resistance and natural products that are promising leads for the development of novel chemotherapeutics.

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Biochemical alterations in paromomycin-treated Leishmania donovani promastigotes

Cited by 62 publications

References 16 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

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

Leishmaniasis: Drug resistance and natural products (Review)

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