Sensitivity of Leishmania spp. to Glibenclamide and 4-Aminopiridine: A Tool for the Study of Drug Resistance Development

Ponte-Sucre, Alicia; Campos, Yelitza; Vázquez, Jorge; Moll, Heidrun; Mendoza-León, Alexis

doi:10.1590/s0074-02761997000500007

Cited by 12 publications

(14 citation statements)

References 13 publications

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“…Aside from an effect on the inflammasome, Hamon et al have presented evidence that glyburide may block the secretion of mature IL1β by an inflammasome-independent mechanism [11]. Glyburide has also been shown to have other anti-inflammatory effects, including the prevention of ischemic reperfusion injury [58], [59], and an enhancement of intracellular killing of Leishmania parasites [60].…”

Section: Discussionmentioning

confidence: 99%

Glyburide Reduces Bacterial Dissemination in a Mouse Model of Melioidosis

et al. 2013

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Background Burkholderia pseudomallei infection (melioidosis) is an important cause of community-acquired Gram-negative sepsis in Northeast Thailand, where it is associated with a ∼40% mortality rate despite antimicrobial chemotherapy. We showed in a previous cohort study that patients taking glyburide ( = glibenclamide) prior to admission have lower mortality and attenuated inflammatory responses compared to patients not taking glyburide. We sought to define the mechanism underlying this observation in a murine model of melioidosis.MethodsMice (C57BL/6) with streptozocin-induced diabetes were inoculated with ∼6×102 cfu B. pseudomallei intranasally, then treated with therapeutic ceftazidime (600 mg/kg intraperitoneally twice daily starting 24 h after inoculation) in order to mimic the clinical scenario. Glyburide (50 mg/kg) or vehicle was started 7 d before inoculation and continued until sacrifice. The minimum inhibitory concentration of glyburide for B. pseudomallei was determined by broth microdilution. We also examined the effect of glyburide on interleukin (IL) 1β by bone-marrow-derived macrophages (BMDM).ResultsDiabetic mice had increased susceptibility to melioidosis, with increased bacterial dissemination but no effect was seen of diabetes on inflammation compared to non-diabetic controls. Glyburide treatment did not affect glucose levels but was associated with reduced pulmonary cellular influx, reduced bacterial dissemination to both liver and spleen and reduced IL1β production when compared to untreated controls. Other cytokines were not different in glyburide-treated animals. There was no direct effect of glyburide on B. pseudomallei growth in vitro or in vivo. Glyburide directly reduced the secretion of IL1β by BMDMs in a dose-dependent fashion.ConclusionsDiabetes increases the susceptibility to melioidosis. We further show, for the first time in any model of sepsis, that glyburide acts as an anti-inflammatory agent by reducing IL1β secretion accompanied by diminished cellular influx and reduced bacterial dissemination to distant organs. We found no evidence for a direct effect of glyburide on the bacterium.

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Section: Discussionmentioning

confidence: 99%

Glyburide Reduces Bacterial Dissemination in a Mouse Model of Melioidosis

et al. 2013

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“…Promastigotes of Leishmania NR were grown as described (Eresh et al 1993;Mendoza-LeoÂ n et al 1995). The resistant strain NR(Gr), was selected in vitro by successive passages of the sensitive strain grown in the presence of 16 lM GLIB as previously described (Ponte-Sucre et al 1997) and maintained under pressure of the drug.…”

Section: Drugs Strains and Culture Conditionsmentioning

confidence: 99%

“…At the end of the incubation time, the number of live cells was quanti®ed bȳ uorescence microscopy at 495 nm after staining with¯uorescein diacetate (Ponte-Sucre et al 1997) and was compared to the number of live cells in control vials of NR(Gs) incubated without GLIB.…”

Section: Drugs Strains and Culture Conditionsmentioning

confidence: 99%

“…In an eort to understand whether the action of GLIB on Leishmania is targeted to Pgp, we experimentally selected a GLIB resistant Venezuelan Leishmania strain NR [NR(Gr)] and initiated the molecular characterization of the mechanisms involved in the expression of this phenotype. The development of resistance to GLIB was found to be associated with the ampli®cation of DNA sequences probably related to ltpgpA (Ponte-Sucre et al 1997) in L. tarentolae (LeÂ gareÂ et al 1994) but might also involve other mechanisms. Therefore, the aim of this study was to evaluate the correlation between the expression of GLIB resistance and functional parameters, such as the infectivity of the parasite, the expression of Pgp and the activities of key enzymes, such as acid phosphatase and pyruvate kinase.…”

Section: Introductionmentioning

confidence: 99%

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Changes in the infectivity, pyruvate kinase activity, acid phosphatase activity and P-glycoprotein expression in glibenclamide-resistant Leishmania mexicana

Garcia

Figarella

Mendoza-León

et al. 2000

Parasitology Research

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We previously demonstrated susceptibility of Leishmania sp. to glibenclamide, a K+ -ATP transport blocker which interacts with members of the superfamily of adenosine 5' triphosphate-binding cassette transporters. In order to characterize the molecular differences between a sensitive Leishmania strain, NR(Gs), and an experimentally selected glibenclamide-resistant strain, NR(Gr), specific biochemical and functional parameters have been evaluated both in the wild type and in the resistant strain. Most noteworthy, NR(Gr) exhibit an increased expression of P-glycoprotein and a decreased activity of functional key enzymes such as acid phosphatase, a prominent virulent factor of the parasite, and pyruvate kinase, a key control enzyme for both carbohydrate and protein metabolism. The specific biochemical, metabolic and functional changes observed in the resistant strain correlated with a reduced infectivity of stationary phase NR(Gr) in J774 macrophages and suggested a mechanism to overcome the effect of glibenclamide.

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“…A DNA fragment which hybridized to ltpgpA and showed size polymorphism between the sensitive and the resistant strain was amplified [46] in L. mexicana made resistant to glibenclamide – a general blocker of ABC transporters including P-gp from different drug-resistant cell lines [45]. This amplification correlates with increased expression of a 185 kDa protein band in the resistant strain, faintly expressed in the sensitive strain [47], that was recognized by the antibody (F4) against the N-terminal of P-gp.…”

Section: Genomic Events Associated With Drug-resistance In Leishmaniamentioning

confidence: 99%

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Ponte-Sucre

2003

Kinetoplastid Biol Dis

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In the early twentieth century, infectious diseases were a leading cause of death worldwide. Through the following years, morbidity and mortality caused by infectious diseases decreased considerably in the developed world, but not in the developing world, where infectious diseases remain an important reason for concern. For example, leishmaniosis has become into a serious Third World problem. This is mainly due to an increasing frequency of drug-resistance in Leishmania and an enhanced risk of co-infection with HIV. Drug-resistance is usually associated with an increased expression of specific P-glycoproteins involved in membrane transport. The present review summarizes information which shows that drug-resistance is also associated with changes in physiological events such as parasite infectivity, incorporation of metabolites, xenobiotics conjugation and traffic, intracellular metabolism, host-parasite interaction, parasite cell shape and promastigote-amastigote differentiation. Furthermore, these events may change in a coordinated manner. An understanding of these physiological events may be helpful for designing chemotherapeutic approaches to multiple cellular targets, identifying strategies to circumvent Leishmania drug-resistance and succesfully treating leishmaniosis.

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Sensitivity of Leishmania spp. to Glibenclamide and 4-Aminopiridine: A Tool for the Study of Drug Resistance Development

Cited by 12 publications

References 13 publications

Glyburide Reduces Bacterial Dissemination in a Mouse Model of Melioidosis

Glyburide Reduces Bacterial Dissemination in a Mouse Model of Melioidosis

Changes in the infectivity, pyruvate kinase activity, acid phosphatase activity and P-glycoprotein expression in glibenclamide-resistant Leishmania mexicana

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