Chemotherapeutics of visceral leishmaniasis: present and future developments

Sundar, Shyam; Singh, Anup

doi:10.1017/s0031182017002116

Cited by 111 publications

(86 citation statements)

References 85 publications

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“…Regardless of Leishmania species or host cell types, the general order of drug susceptibility was, from high to low susceptibility, AmpB, miltefosine, SSG, and paromomycin, consistent with susceptibility data previously reported [35,43]. Though it is difficult to draw a direct correlation between the sequences of in vitro potency to the clinical efficacy of each drug due to their pharmacokinetics property and tissue distribution in humans, it is at least worth mentioning that the least potent drug in vitro, paromomycin, showed varying ranges of efficacy in clinical studies [44]. When we consider these three points, we suggest using THP-1 for L. donovani infections, and BMDM (or alternatively THP-1) for L. amazonensis with amastigotes as the form of parasite.…”

Section: Discussionsupporting

confidence: 87%

Infectivity and Drug Susceptibility Profiling of Different Leishmania-Host Cell Combinations

et al. 2020

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Protozoan parasites of the genus Leishmania are the causative agents of leishmaniasis, a spectrum of a disease that threatens public health worldwide. Although next-generation therapeutics are urgently needed, the early stage of the drug discovery process is hampered by very low hit rates from intracellular Leishmania phenotypic high-throughput screenings. Designing and applying a physiologically relevant in vitro assay is therefore in high demand. In this study, we characterized the infectivity, morphology, and drug susceptibility of different Leishmania and host cell infection combinations. Primary bone marrow-derived macrophage (BMDM) and differentiated human acute monocytic leukemia (THP-1) cells were infected with amastigote or promastigote forms of Leishmania amazonensis and Leishmania donovani. Regardless of host cell types, amastigotes were generally well phagocytosed and showed high infectivity, whereas promastigotes, especially those of L. donovani, had predominantly remained in the extracellular space. In the drug susceptibility test, miltefosine and sodium stibogluconate (SSG) showed varying ranges of activity with 14 and >10-fold differences in susceptibility, depending on the host-parasite pairs, indicating the importance of assay conditions for evaluating antileishmanial activity. Overall, our results suggest that combinations of Leishmania species, infection forms, and host cells must be carefully optimized to evaluate the activity of potential therapeutic compounds against Leishmania.

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Section: Discussionsupporting

confidence: 87%

Infectivity and Drug Susceptibility Profiling of Different Leishmania-Host Cell Combinations

et al. 2020

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“…The clinical symptomatology of this disease depends on the infective species of Leishmania and on the immunological status of the host, ranging from the usually mild cutaneous forms of the disease to the visceral syndrome, which is highly lethal if untreated (1). Leishmaniasis accounts for 10 to 12 million infected people worldwide and nearly 50,000 deaths per year in 98 countries where the disease is endemic (2).…”

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confidence: 99%

Molecular Basis of the Leishmanicidal Activity of the Antidepressant Sertraline as a Drug Repurposing Candidate

Lima

Abengózar

Nachér-Vázquez

et al. 2018

Antimicrob Agents Chemother

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Drug repurposing affords the implementation of new treatments at a moderate cost and under a faster time-scale. Most of the clinical drugs againstLeishmaniashare this origin. The antidepressant sertraline has been successfully assayed in a murine model of visceral leishmaniasis. Nevertheless, sertraline targets inLeishmaniawere poorly defined. In order to get a detailed insight into the leishmanicidal mechanism of sertraline onLeishmania infantum, unbiased multiplatform metabolomics and transmission electron microscopy were combined with a focused insight into the sertraline effects on the bioenergetics metabolism of the parasite. Sertraline induced respiration uncoupling, a significant decrease of intracellular ATP level, and oxidative stress inL. infantumpromastigotes. Metabolomics evidenced an extended metabolic disarray caused by sertraline. This encompasses a remarkable variation of the levels of thiol-redox and polyamine biosynthetic intermediates, as well as a shortage of intracellular amino acids used as metabolic fuel byLeishmania. Sertraline killedLeishmaniathrough a multitarget mechanism of action, tackling essential metabolic pathways of the parasite. As such, sertraline is a valuable candidate for visceral leishmaniasis treatment under a drug repurposing strategy.

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“…Amphotericin B-liposome (AmBisome®), a superior but expensive drug, is limited in use in endemic areas of poverty. Appearance and spread of drug resistance is also a major cause of concern hence, as extensively reviewed in this special issue (Sundar and Singh, 2018). Strategies for boosting hosts’ immune responses to potentiate chemotherapy are considered as important future tools to meet such challenges and are reviewed by Taslimi et al (2018) in this special issue.…”

Section: Clinical Management Of Leishmaniasismentioning

confidence: 99%

Leishmaniasis: current challenges and prospects for elimination with special focus on the South Asian region

Karunaweera

Ferreira

2018

Parasitology

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SUMMARY Leishmania donovani, arguably the most virulent species of Leishmania, is found in the South Asian region that harbor the majority of visceral leishmaniasis (VL) cases in the world. The traditionally accepted relationships between the causative species of Leishmania and the resultant disease phenotype have been challenged during recent years and has underscored the importance of revisiting the previously established taxonomy with revisions to its classification. The weak voice of the afflicted with decades of neglect by scientists and policy makers have led to the miserably inadequate and slow advancements in product development in the fields of diagnostics, chemotherapeutics and vector control that continue to hinder the effective management and control of this infection. Limitations notwithstanding, the regional drive for elimination of VL initiated over a decade ago that focused on India, Nepal and Bangladesh, the three main afflicted countries in the Indian subcontinent is therefore, commendable, with the subsequent status reviews and restructuring of strategies possibly even more so. However, the renewed efforts would need to be combined with plans to combat new challenges in the south-Asian region that includes the emergence of atypical parasite variants, in order to realistically achieve the set goal of regional elimination of VL.

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Chemotherapeutics of visceral leishmaniasis: present and future developments

Cited by 111 publications

References 85 publications

Infectivity and Drug Susceptibility Profiling of Different Leishmania-Host Cell Combinations

Infectivity and Drug Susceptibility Profiling of Different Leishmania-Host Cell Combinations

Molecular Basis of the Leishmanicidal Activity of the Antidepressant Sertraline as a Drug Repurposing Candidate

Leishmaniasis: current challenges and prospects for elimination with special focus on the South Asian region

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