In vitro and in vivo pharmacodynamics of three novel antileishmanial lead series

The protozoan parasite Leishmania causes leishmaniasis; a spectrum of diseases of which there are an estimated 1 million new cases each year. Current treatments are toxic, expensive, difficult to administer, and resistance to them is emerging. New therapeutics are urgently needed, however, screening the infective amastigote form of the parasite is challenging. Only certain species can be differentiated into axenic amastigotes, and compound activity against these does not always correlate with efficacy against the parasite in its intracellular niche. Methods used to assess compound efficacy on intracellular amastigotes often rely on microscopy-based assays. These are laborious, require specialist equipment and can only determine parasite burden, not parasite viability. We have addressed this clear need in the anti-leishmanial drug discovery process by producing a transgenic L. mexicana cell line that expresses the luciferase NanoLuc-PEST. We tested the sensitivity and versatility of this transgenic strain, in comparison with strains expressing NanoLuc and the red-shifted firefly luciferase. We then compared the NanoLuc-PEST luciferase to the current methods in both axenic and intramacrophage amastigotes following treatment with a supralethal dose of Amphotericin B. NanoLuc-PEST was a more dynamic indicator of cell viability due to its high turnover rate and high signal:background ratio. This, coupled with its sensitivity in the intramacrophage assay, led us to validate the NanoLuc-PEST expressing cell line using the MMV Pathogen Box in a two-step process: i) identify hits against axenic amastigotes, ii) screen these hits using our bioluminescence-based intramacrophage assay. The data obtained from this highlights the potential of compounds active against M. tuberculosis to be re-purposed for use against Leishmania. Our transgenic L. mexicana cell line is therefore a highly sensitive and dynamic system suitable for Leishmania drug discovery in axenic and intramacrophage amastigote models.

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“…This has yielded success with the identification of three new chemical series that display considerable anti-leishmanial potential. [ 5 ]…”

Section: Introductionmentioning

confidence: 99%

Development of NanoLuc-PEST expressing Leishmania mexicana as a new drug discovery tool for axenic- and intramacrophage-based assays

et al. 2018

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“…At present, drug repurposing strategies strongly contribute to the quest for new and better leishmaniasis treatments. Nitroheterocyclic compounds such as fexinidazole, oxaboroles, and delamanide (17), formerly reported as African trypanocidal, antifungal, and antimycobacterial agents, respectively, or the antitumoral aminopyrazole are or have been under trial as new clinical leishmanicidal drugs (18,19).…”

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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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“…Currently, the main drugs for leishmaniasis are pentavalent antimonial and amphotericin B. Regarding high cost and long treatment periods, side effects, high toxicity to heart, liver, and kidneys, risk of relapse, and resistance of some Leishmania species, investigation of natural medicaments is increasing (11,28). Medicinal herbs for the treatment of parasitic diseases have been studied for a long time (29).…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo Assessment of Anti-Leishmanial Efficacy of Leaf, Fruit, and Fractions of Juniperus excelsa Against Axenic Amastigotes of Leishmania major and Topical Formulation in BALB/c Mice

Mirzavand¹,

Hatam²,

Moein³

et al. 2019

Iran Red Crescent Med J

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Background: Leishmaniasis is a parasitic disease caused by Leishmania protozoa. Iran is an endemic region for leishmaniasis and thus, many natural medicaments, such as Juniperus excelsa, are traditionally being used for the treatment of its cutaneous form. Objectives: The current study aimed at assessing the anti-leishmanial activities of this medicament's leaf and fruit extracts and respective leaf fractions against Leishmania major as the causative agent of zoonotic cutaneous leishmaniasis in both in vitro and in vivo models.

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In vitro and in vivo pharmacodynamics of three novel antileishmanial lead series

Cited by 40 publications

References 36 publications

Development of NanoLuc-PEST expressing Leishmania mexicana as a new drug discovery tool for axenic- and intramacrophage-based assays

Development of NanoLuc-PEST expressing Leishmania mexicana as a new drug discovery tool for axenic- and intramacrophage-based assays

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

In vitro and in vivo Assessment of Anti-Leishmanial Efficacy of Leaf, Fruit, and Fractions of Juniperus excelsa Against Axenic Amastigotes of Leishmania major and Topical Formulation in BALB/c Mice

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