Leishmaniasis in the major endemic region of Plurinational State of Bolivia: Species identification, phylogeography and drug susceptibility implications

Bilbao-Ramos, Pablo; Dea-Ayuela, María Auxiliadora; Cardenas-Alegría, Oscar Victor; Salamanca, Efraín; Santalla-Vargas, José Antonio; Benito, C.; Flores, Ninoska; Bolás‐Fernández, F.

doi:10.1016/j.actatropica.2017.07.026

Cited by 18 publications

(14 citation statements)

References 81 publications

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“…Anti-leishmanial drug-resistance is an increasing concern in Colombia, but also worldwide (45–47). In India miltefosine has replaced antimony as the first line of treatment against visceral leishmaniasis due to widespread evidence of antimony-resistance (48).…”

Section: Discussionmentioning

confidence: 99%

Resistance of Leishmania (Viannia) Panamensis to Meglumine Antimoniate or Miltefosine Modulates Neutrophil Effector Functions

et al. 2018

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Leishmania (Viannia) panamensis (L. (V.) p.) is the main causative agent of cutaneous leishmaniasis in Colombia and is usually treated with either meglumine antimoniate (MA) or miltefosine (MIL). In recent years, there has been increasing evidence of the emergence of drug-resistance against these compounds. Neutrophils are known to play an important role in immunity against Leishmania. These cells are rapidly recruited upon infection and are also present in chronic lesions. However, their involvement in the outcome of infection with drug-resistant Leishmania has not been examined. In this study, human and murine neutrophils were infected in vitro with MA or MIL drug-resistant L. (V.) p. lines derived from a parental L. (V.) p. drug-susceptible strain. Neutrophil effector functions were assessed analyzing the production of reactive oxygen species (ROS), the formation of neutrophil extracellular trap (NET) and the expression of cell surface activation markers. Parasite killing by neutrophils was assessed using L. (V.) p. transfected with a luciferase reporter. We show here that MA and MIL-resistant L. (V.) p. lines elicited significantly increased NET formation and MA-resistant L. (V.) p. induced significantly increased ROS production in both murine and human neutrophils, compared to infections with the parental MIL and MA susceptible strain. Furthermore, neutrophils exposed to drug-resistant lines showed increased activation, as revealed by decreased expression of CD62L and increased expression of CD66b in human neutrophils yet presented higher survival within neutrophils than the drug-susceptible strain. These results provide evidence that parasite drug-susceptibility may influences neutrophil activation and function as well as parasite survival within neutrophils. Further investigaton of the inter-relationship of drug susceptibility and neutrophil effector function should contribute to better understanding of the factors involved in susceptibility to anti-Leishmania drugs.

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Section: Discussionmentioning

confidence: 99%

Resistance of Leishmania (Viannia) Panamensis to Meglumine Antimoniate or Miltefosine Modulates Neutrophil Effector Functions

et al. 2018

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“…Evaluations against Leishmania parasites: Promastigotes of Leishmania-Leishmania: L. amazonensis , Clone 1, NHOM-BR-76-LTB-012 (Lma, donated by the Paul Sabatier Université, France) and Leishmania-Viannia: L. braziliensis M2904 C192 RJA (M2904, donated by Dr. Jorge Arévalo from Universidad Peruana Cayetano Heredia, Peru) [ 26 ]. All strains were cultured in Schneider’s insect medium, (pH 6.2) supplemented with 10% FBS and incubated at 26 °C.…”

Section: Methodsmentioning

confidence: 99%

SAR:s for the Antiparasitic Plant Metabolite Pulchrol. 1. The Benzyl Alcohol Functionality

et al. 2020

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Pulchrol (1) is a natural benzochromene isolated from the roots of Bourreria pulchra, shown to possess potent antiparasitic activity towards both Leishmania and Trypanozoma species. As it is not understood which molecular features of 1 are important for the antiparasitic activity, several analogues were synthesized and assayed. The ultimate goal is to understand the structure–activity relationships (SAR:s) and create a QSAR model that can be used for the development of clinically useful antiparasitic agents. In this study, we have synthesized 25 2-methoxy-6,6-dimethyl-6H-benzo[c]chromen analogues of 1 and its co-metabolite pulchral (5a), by semi-synthetic procedures starting from the natural product pulchrol (1) itself. All 27 compounds, including the two natural products 1 and 5a, were subsequently assayed in vitro for antiparasitic activity against Trypanozoma cruzi, Leishmania brasiliensis and Leishmania amazoniensis. In addition, the cytotoxicity in RAW cells was assayed, and a selectivity index (SI) for each compound and each parasite was calculated. Several compounds are more potent or equi-potent compared with the positive controls Benznidazole (Trypanozoma) and Miltefosine (Leishmania). The compounds with the highest potencies as well as SI-values are esters of 1 with various carboxylic acids.

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“…Promastigotes of Leishmania-Leishmania: L. amazonensis , Clone 1, NHOM-BR-76-LTB-012 (Lma, donated by the Paul Sabatier Université, Toulouse, France) and Leishmania-Viannia: L. braziliensis M2904 C192 RJA (M2904, donated by Dr. Jorge Arévalo from Universidad Peruana Cayetano Heredia, San Martin des Porres, Peru), [ 30 ]. All strains were cultured in Schneider’s insect medium, (pH 6.2) supplemented with 10% FBS and incubated at 26 °C.…”

Section: Methodsmentioning

confidence: 99%

SARs for the Antiparasitic Plant Metabolite Pulchrol. Part 2: B- and C-Ring Substituents

et al. 2020

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Neglected tropical diseases affect most of the underprivileged populations in tropical countries. Among these are chagas and leishmaniasis, present mainly in South and Central America, Africa and East Asia. Current treatments are long and have severe adverse effects, therefore there is a strong need to develop alternatives. In this study, we base our research on the plant metabolite pulchrol, a natural benzochromene which has been shown to possess antiparasitic activity against Trypanosoma and Leishmania species. In a recent study, we investigated how changes in the benzyl alcohol functionality affected the antiparasitic activity, but the importance of B- and C-ring substituents is not understood. Fifteen derivatives of pulchrol with different substituents in positions 1, 2, 3, and 6 while leaving the A-ring intact, were therefore prepared by total synthesis, assayed, and compared with pulchrol and positive controls. The generated series and parental molecule were tested in vitro for antiparasitic activity against Trypanosoma cruzi, Leishmania braziliensis, and L. amazonensis, and cytotoxicity using RAW cells. Substantial differences in the activity of the compounds synthesized were observed, of which some were more potent towards Trypanosoma cruzi than the positive control benznidazole. A general tendency is that alkyl substituents improve the potency, especially when positioned on C-2.

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Leishmaniasis in the major endemic region of Plurinational State of Bolivia: Species identification, phylogeography and drug susceptibility implications

Cited by 18 publications

References 81 publications

Resistance of Leishmania (Viannia) Panamensis to Meglumine Antimoniate or Miltefosine Modulates Neutrophil Effector Functions

Resistance of Leishmania (Viannia) Panamensis to Meglumine Antimoniate or Miltefosine Modulates Neutrophil Effector Functions

SAR:s for the Antiparasitic Plant Metabolite Pulchrol. 1. The Benzyl Alcohol Functionality

SARs for the Antiparasitic Plant Metabolite Pulchrol. Part 2: B- and C-Ring Substituents

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