Chemotherapy of Leishmania and Trypanosoma Infections: Lost in Translation?

A special issue of Microorganisms (ISSN 2076-2607). This special issue belongs to the section "Parasitology".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 19226

Special Issue Editor

Department of Animal Health, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, Madrid, Spain
Interests: Leishmania; Trypanosoma; chemotherapy; immunology; pathophysiology; pharmacology; parasites; vaccination; dog; ruminants; translational therapeutics; new drugs; drug delivery systems
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Special Issue Information

Dear Colleagues,

Infections by the kinetoplastidsTrypanosoma and Leishmania are widespread, causing debilitating or deadly processes and affecting a variety of hosts, including humans. Some species are zoonotic and both domestic and wild hosts can be infected, providing uncontrolled infection reservoirs. Naturally occurring vectoral transmission makes the environmental control virtually unfeasible in most cases; vaccination is unavailable or very limited, and the reduction of infection level and its extension relies mainly on chemotherapy. The therapeutic arsenal is very limited and of variable efficacy depending on the kinetoplastid species involved or even the developmental stage. Most of the available drugs have toxicity issues and with few exceptions were synthesized over 50 years ago. Very few new chemical entities (NCE) are foreseen, and resistance to the commonly used drugs has been increasingly been reported. Exploratory studies are largely carried out by academia given the low revenues expected by industry. Strategies to cope with the shortage of NCE include the development of drug delivery systems, combination of available drugs, and target-based exploration combined with high-throughput drug screening. Insofar, current therapeutics involves, as a rule, the same compounds available along the second half of the 20th century.

Reports on the identification of new targets in the parasites and new molecules of potential value are abundant. However, the effective progress of these molecules along the drug pipeline has been negligible. Several causes for the scarcity of NCE and the high attrition rate of the candidates could be invoked. Among them, the inherent difficulty involved, the complexity of life cycles or the inadequate surrogate models for drug screening have been incriminated. There are other issues receiving lower consideration that could be relevant to reduce the high numbers of molecules of potential values never tested in adequate models or “drug killing” in the so-called Valley of Death in drug discovery.

Potential topics for this issue include, but are not restricted to, research papers or reviews on pharmacology-driven selection of molecules for the treatment of Leishmania and Trypanosoma infections, knowledge of pathophysiology of the diseases and its effect on drug availability and efficacy, improvement of the identification of predictive markers of efficacy, drug delivery systems and their value beyond laboratory, standardization of efficacy trials, relative value of in vitro, ex vivo and in vivo models for drug exploration, impact of microbiome on efficacy, immune modulation to improve drug efficacy, and strategies to minimize drug resistance emergence and extension.

Therapy of these life-threatening human and animal diseases is challenging, but the reward is high. I hope you find the topic attractive and that your contribution can help to develop effective and affordable drugs.

Prof. Dr. José Ma. Alunda
Guest Editor

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Keywords

  • Leishmania
  • Trypanosoma
  • pharmacology
  • therapeutics
  • screening
  • drugs
  • molecules
  • high-throughput systems
  • target-based drug selection
  • in vitro
  • in vivo
  • ex vivo
  • animal models
  • dogs
  • cattle
  • humans
  • resistance

Related Special Issue

Published Papers (8 papers)

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Editorial

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7 pages, 254 KiB  
Editorial
Antileishmanial and Antitrypanosomes Drugs for the Current Century
Microorganisms 2024, 12(1), 43; https://doi.org/10.3390/microorganisms12010043 - 26 Dec 2023
Viewed by 653
Abstract
Human infections by trypanosomatids are widely distributed and prevalent in the tropical and subtropical regions. Diseases caused by Trypanosoma and Leishmania have variable clinical outcomes, ranging from self-healing to fatality, and are considered Neglected Tropical Diseases (NTD). In addition, animal trypanosomiases have a [...] Read more.
Human infections by trypanosomatids are widely distributed and prevalent in the tropical and subtropical regions. Diseases caused by Trypanosoma and Leishmania have variable clinical outcomes, ranging from self-healing to fatality, and are considered Neglected Tropical Diseases (NTD). In addition, animal trypanosomiases have a significant impact on animal health and production, apart from their potential role as reservoirs in zoonotic species. Control of these infections is progressing and, in some cases (such as human African trypanomiasis (HAT)), significant reductions have been achieved. In the absence of effective vaccination, chemotherapy is the most used control method. Unfortunately, the therapeutic arsenal is scarce, old, and of variable efficacy, and reports of resistance to most antiparasitic agents have been published. New drugs, formulations, or combinations are needed to successfully limit the spread and severity of these diseases within a One Health framework. In this Special Issue, contributions regarding the identification and validation of drug targets, underlying mechanisms of action and resistance, and potential new molecules are presented. These research contributions are complemented by an update revision of the current chemotherapy against African Trypanosoma species, and a critical review of the shortcomings of the prevailing model of drug discovery and development. Full article

Research

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20 pages, 2359 KiB  
Article
Simvastatin Resistance of Leishmania amazonensis Induces Sterol Remodeling and Cross-Resistance to Sterol Pathway and Serine Protease Inhibitors
Microorganisms 2022, 10(2), 398; https://doi.org/10.3390/microorganisms10020398 - 09 Feb 2022
Cited by 2 | Viewed by 1902
Abstract
The sterol biosynthesis pathway of Leishmania spp. is used as a pharmacological target; however, available information about the mechanisms of the regulation and remodeling of sterol-related genes is scarce. The present study investigated compensatory mechanisms of the sterol biosynthesis pathway using an inhibitor [...] Read more.
The sterol biosynthesis pathway of Leishmania spp. is used as a pharmacological target; however, available information about the mechanisms of the regulation and remodeling of sterol-related genes is scarce. The present study investigated compensatory mechanisms of the sterol biosynthesis pathway using an inhibitor of HMG-CoA reductase (simvastatin) and by developing drug-resistant parasites to evaluate the impact on sterol remodeling, cross-resistance, and gene expression. Simvastatin-resistant L. amazonensis parasites (LaSimR) underwent reprogramming of sterol metabolism manifested as an increase in cholestane- and stigmastane-based sterols and a decrease in ergostane-based sterols. The levels of the transcripts of sterol 24-C-methyltransferase (SMT), sterol C14-α-demethylase (C14DM), and protease subtilisin (SUB) were increased in LaSimR. LaSimR was cross-resistance to ketoconazole (a C14DM inhibitor) and remained sensitive to terbinafine (an inhibitor of squalene monooxygenase). Sensitivity of the LaSimR mutant to other antileishmanial drugs unrelated to the sterol biosynthesis pathway, such as trivalent antimony and pentamidine, was similar to that of the wild-type strain; however, LaSimR was cross-resistant to miltefosine, general serine protease inhibitor N-p-tosyl-l-phenylalanine chloromethyl ketone (TPCK), subtilisin-specific inhibitor 4-[(diethylamino)methyl]-N-[2-(2-methoxyphenyl)ethyl]-N-(3R)-3-pyrrolidinyl-benzamide dihydrochloride (PF-429242), and tunicamycin. The findings on the regulation of the sterol pathway can support the development of drugs and protease inhibitors targeting this route in parasites. Full article
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12 pages, 2166 KiB  
Communication
Minor Impact of A258D Mutation on Biochemical and Enzymatic Properties of Leishmania infantum GDP-Mannose Pyrophosphorylase
Microorganisms 2022, 10(2), 231; https://doi.org/10.3390/microorganisms10020231 - 21 Jan 2022
Cited by 2 | Viewed by 1470
Abstract
Background: Leishmaniasis, a vector-borne disease caused by the protozoan parasite from the genus Leishmania, is endemic to tropical and subtropical areas. Few treatments are available against leishmaniasis, with all presenting issues of toxicity, resistance, and/or cost. In this context, the development of [...] Read more.
Background: Leishmaniasis, a vector-borne disease caused by the protozoan parasite from the genus Leishmania, is endemic to tropical and subtropical areas. Few treatments are available against leishmaniasis, with all presenting issues of toxicity, resistance, and/or cost. In this context, the development of new antileishmanial drugs is urgently needed. GDP-mannose pyrophosphorylase (GDP-MP), an enzyme involved in the mannosylation pathway, has been described to constitute an attractive therapeutic target for the development of specific antileishmanial agents. Methods: In this work, we produced, purified, and analyzed the enzymatic properties of the recombinant L. infantum GDP-MP (LiGDP-MP), a single leishmanial GDP-MP that presents mutation of an aspartate instead of an alanine at position 258, which is also the single residue difference with the homolog in L. donovani: LdGDP-MP. Results: The purified LiGDP-MP displayed high substrate and cofactor specificities, a sequential random mechanism of reaction, and the following kinetic constants: Vm at 0.6 µM·min−1, Km from 15–18 µM, kcat from 12.5–13 min−1, and kcat/Km at around 0.8 min−1µM−1. Conclusions: These results show that LiGDP-MP has similar biochemical and enzymatic properties to LdGDP-MP. Further studies are needed to determine the advantage for L. infantum of the A258D residue change in GDP-MP. Full article
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14 pages, 2873 KiB  
Article
Experimental Selection of Paromomycin Resistance in Leishmania donovani Amastigotes Induces Variable Genomic Polymorphisms
Microorganisms 2021, 9(8), 1546; https://doi.org/10.3390/microorganisms9081546 - 21 Jul 2021
Cited by 6 | Viewed by 2242
Abstract
The relatively high post-treatment relapse rates of paromomycin (PMM) in visceral leishmaniasis treatment and the swift emergence of experimental drug resistance challenge its broad application and urge for rational use and monitoring of resistance. However, no causal molecular mechanisms to Leishmania PMM resistance [...] Read more.
The relatively high post-treatment relapse rates of paromomycin (PMM) in visceral leishmaniasis treatment and the swift emergence of experimental drug resistance challenge its broad application and urge for rational use and monitoring of resistance. However, no causal molecular mechanisms to Leishmania PMM resistance have been identified so far. To gain insights into potential resistance mechanisms, twelve experimentally selected Leishmania donovani clonal lines and the non-cloned preselection population, with variable degrees of PMM resistance, were subjected to whole genome sequencing. To identify genomic variations potentially associated with resistance, SNPs, Indels, chromosomal somy and gene copy number variations were compared between the different parasite lines. A total of 11 short nucleotide variations and the copy number alterations in 39 genes were correlated to PMM resistance. Some of the identified genes are involved in transcription, translation and protein turn-over (transcription elongation factor-like protein, RNA-binding protein, ribosomal protein L1a, 60S ribosomal protein L6, eukaryotic translation initiation factor 4E-1, proteasome regulatory non-ATP-ase subunit 3), virulence (major surface protease gp63, protein-tyrosine phosphatase 1-like protein), mitochondrial function (ADP/ATP mitochondrial carrier-like protein), signaling (phosphatidylinositol 3-related kinase, protein kinase putative and protein-tyrosine phosphatase 1-like protein) and vesicular trafficking (ras-related protein RAB1). These results indicate that, in Leishmania, the aminoglycoside PMM affects protein translational processes and underlines the complex and probably multifactorial origin of resistance. Full article
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16 pages, 6336 KiB  
Article
4E Interacting Protein as a Potential Novel Drug Target for Nucleoside Analogues in Trypanosoma brucei
Microorganisms 2021, 9(4), 826; https://doi.org/10.3390/microorganisms9040826 - 13 Apr 2021
Cited by 5 | Viewed by 2212
Abstract
Human African trypanosomiasis is a neglected parasitic disease for which the current treatment options are quite limited. Trypanosomes are not able to synthesize purines de novo and thus solely depend on purine salvage from the host environment. This characteristic makes players of the [...] Read more.
Human African trypanosomiasis is a neglected parasitic disease for which the current treatment options are quite limited. Trypanosomes are not able to synthesize purines de novo and thus solely depend on purine salvage from the host environment. This characteristic makes players of the purine salvage pathway putative drug targets. The activity of known nucleoside analogues such as tubercidin and cordycepin led to the development of a series of C7-substituted nucleoside analogues. Here, we use RNA interference (RNAi) libraries to gain insight into the mode-of-action of these novel nucleoside analogues. Whole-genome RNAi screening revealed the involvement of adenosine kinase and 4E interacting protein into the mode-of-action of certain antitrypanosomal nucleoside analogues. Using RNAi lines and gene-deficient parasites, 4E interacting protein was found to be essential for parasite growth and infectivity in the vertebrate host. The essential nature of this gene product and involvement in the activity of certain nucleoside analogues indicates that it represents a potential novel drug target. Full article
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18 pages, 1015 KiB  
Article
Leishmanicidal Activity of Betulin Derivatives in Leishmania amazonensis; Effect on Plasma and Mitochondrial Membrane Potential, and Macrophage Nitric Oxide and Superoxide Production
Microorganisms 2021, 9(2), 320; https://doi.org/10.3390/microorganisms9020320 - 04 Feb 2021
Cited by 4 | Viewed by 2091
Abstract
Herein, we evaluated in vitro the anti-leishmanial activity of betulin derivatives in Venezuelan isolates of Leishmania amazonensis, isolated from patients with therapeutic failure. Methods: We analyzed promastigote in vitro susceptibility as well as the cytotoxicity and selectivity of the evaluated compounds. Additionally, [...] Read more.
Herein, we evaluated in vitro the anti-leishmanial activity of betulin derivatives in Venezuelan isolates of Leishmania amazonensis, isolated from patients with therapeutic failure. Methods: We analyzed promastigote in vitro susceptibility as well as the cytotoxicity and selectivity of the evaluated compounds. Additionally, the activity of selected compounds was determined in intracellular amastigotes. Finally, to gain hints on their potential mechanism of action, the effect of the most promising compounds on plasma and mitochondrial membrane potential, and nitric oxide and superoxide production by infected macrophages was determined. Results: From the tested 28 compounds, those numbered 18 and 22 were chosen for additional studies. Both 18 and 22 were active (GI50 ≤ 2 µM, cytotoxic CC50 > 45 µM, SI > 20) for the reference strain LTB0016 and for patient isolates. The results suggest that 18 significantly depolarized the plasma membrane potential (p < 0.05) and the mitochondrial membrane potential (p < 0.05) when compared to untreated cells. Although neither 18 nor 22 induced nitric oxide production in infected macrophages, 18 induced superoxide production in infected macrophages. Conclusion: Our results suggest that due to their efficacy and selectivity against intracellular parasites and the potential mechanisms underlying their leishmanicidal effect, the compounds 18 and 22 could be used as tools for designing new chemotherapies against leishmaniasis. Full article
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Review

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24 pages, 6042 KiB  
Review
Current Treatments to Control African Trypanosomiasis and One Health Perspective
Microorganisms 2022, 10(7), 1298; https://doi.org/10.3390/microorganisms10071298 - 27 Jun 2022
Cited by 14 | Viewed by 4477
Abstract
Human African Trypanosomiasis (HAT, sleeping sickness) and Animal African Trypanosomiasis (AAT) are neglected tropical diseases generally caused by the same etiological agent, Trypanosoma brucei. Despite important advances in the reduction or disappearance of HAT cases, AAT represents a risky reservoir of the [...] Read more.
Human African Trypanosomiasis (HAT, sleeping sickness) and Animal African Trypanosomiasis (AAT) are neglected tropical diseases generally caused by the same etiological agent, Trypanosoma brucei. Despite important advances in the reduction or disappearance of HAT cases, AAT represents a risky reservoir of the infections. There is a strong need to control AAT, as is claimed by the European Commission in a recent document on the reservation of antimicrobials for human use. Control of AAT is considered part of the One Health approach established by the FAO program against African Trypanosomiasis. Under the umbrella of the One Health concepts, in this work, by analyzing the pharmacological properties of the therapeutic options against Trypanosoma brucei spp., we underline the need for clearer and more defined guidelines in the employment of drugs designed for HAT and AAT. Essential requirements are addressed to meet the challenge of drug use and drug resistance development. This approach shall avoid inter-species cross-resistance phenomena and retain drugs therapeutic activity. Full article
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18 pages, 393 KiB  
Review
Antileishmanial Drug Discovery and Development: Time to Reset the Model?
Microorganisms 2021, 9(12), 2500; https://doi.org/10.3390/microorganisms9122500 - 02 Dec 2021
Cited by 27 | Viewed by 2824
Abstract
Leishmaniasis is a vector-borne parasitic disease caused by Leishmania species. The disease affects humans and animals, particularly dogs, provoking cutaneous, mucocutaneous, or visceral processes depending on the Leishmania sp. and the host immune response. No vaccine for humans is available, and the control [...] Read more.
Leishmaniasis is a vector-borne parasitic disease caused by Leishmania species. The disease affects humans and animals, particularly dogs, provoking cutaneous, mucocutaneous, or visceral processes depending on the Leishmania sp. and the host immune response. No vaccine for humans is available, and the control relies mainly on chemotherapy. However, currently used drugs are old, some are toxic, and the safer presentations are largely unaffordable by the most severely affected human populations. Moreover, its efficacy has shortcomings, and it has been challenged by the growing reports of resistance and therapeutic failure. This manuscript presents an overview of the currently used drugs, the prevailing model to develop new antileishmanial drugs and its low efficiency, and the impact of deconstruction of the drug pipeline on the high failure rate of potential drugs. To improve the predictive value of preclinical research in the chemotherapy of leishmaniasis, several proposals are presented to circumvent critical hurdles—namely, lack of common goals of collaborative research, particularly in public–private partnership; fragmented efforts; use of inadequate surrogate models, especially for in vivo trials; shortcomings of target product profile (TPP) guides. Full article
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