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Advances in Therapeutics against Eukaryotic Pathogens
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Advances in Therapeutics against Eukaryotic Pathogens

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 November 2024 | Viewed by 6537

Special Issue Editor

Prof. Dr. Edward D’Antonio

E-Mail Website
Guest Editor
Department of Natural Sciences, University of South Carolina Beaufort, Bluffton, SC 29909, USA
Interests: medicinal chemistry; structural biology; biochemistry; Chagas disease; human African trypanosomiasis; leishmaniasis; coronavirus disease; dengue fever; neglected tropical diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Eukaryotic pathogens are responsible for devastating diseases across the world, and, coupled with that, physicians are limited regarding their use of administering efficacious, tolerable, and non-toxic therapeutic options to patients in need. Moreover, given the lack of vaccinations for such diseases, or even the disposition of drug resistance, humankind heavily depends on anti-parasitic drugs. It is often observed that chemical therapeutics with biological activity against one pathogen may also be effective against another, or others. Thus, this Special Issue aims to identify recent advances from therapeutic drug compounds against eukaryotic microorganisms that cause human disease, which will be showcased and discussed. Submissions of experimental or simulated medicinal chemistry research that focus on the development of either known therapeutics and/or the discovery of novel compounds will be of high priority. Since Int. J. Mol. Sci. is dedicated to chemistry and biology at the molecular level, pure clinical studies will not be considered, but clinical submissions with biomolecular experiments are certainly welcomed.

Dr. Edward L. D'Antonio
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • medicinal chemistry
  • parasitology
  • pathogen
  • drug-target
  • NTD
  • cryptosporidia
  • Giardia
  • helminths
  • Leishmania
  • Naegleria
  • Plasmodium
  • Schistosoma
  • Toxoplasma
  • Trichomonas
  • Trypanosoma
 

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Published Papers (4 papers)

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Research

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18 pages, 5871 KiB  
Article
Plasmodium falciparum Mitochondrial Complex III, the Target of Atovaquone, Is Essential for Progression to the Transmissible Sexual Stages
by Pradeep Kumar Sheokand, Sabyasachi Pradhan, Andrew E. Maclean, Alexander Mühleip and Lilach Sheiner
Int. J. Mol. Sci. 2024, 25(17), 9239; https://doi.org/10.3390/ijms25179239 - 26 Aug 2024
Viewed by 462
Abstract
The Plasmodium falciparum mitochondrial electron transport chain (mETC) is responsible for essential metabolic pathways such as de novo pyrimidine synthesis and ATP synthesis. The mETC complex III (cytochrome bc1 complex) is responsible for transferring electrons from ubiquinol to cytochrome c and generating [...] Read more.
The Plasmodium falciparum mitochondrial electron transport chain (mETC) is responsible for essential metabolic pathways such as de novo pyrimidine synthesis and ATP synthesis. The mETC complex III (cytochrome bc1 complex) is responsible for transferring electrons from ubiquinol to cytochrome c and generating a proton gradient across the inner mitochondrial membrane, which is necessary for the function of ATP synthase. Recent studies have revealed that the composition of Plasmodium falciparum complex III (PfCIII) is divergent from humans, highlighting its suitability as a target for specific inhibition. Indeed, PfCIII is the target of the clinically used anti-malarial atovaquone and of several inhibitors undergoing pre-clinical trials, yet its role in parasite biology has not been thoroughly studied. We provide evidence that the universally conserved subunit, PfRieske, and the new parasite subunit, PfC3AP2, are part of PfCIII, with the latter providing support for the prediction of its divergent composition. Using inducible depletion, we show that PfRieske, and therefore, PfCIII as a whole, is essential for asexual blood stage parasite survival, in line with previous observations. We further found that depletion of PfRieske results in gametocyte maturation defects. These phenotypes are linked to defects in mitochondrial functions upon PfRieske depletion, including increased sensitivity to mETC inhibitors in asexual stages and decreased cristae abundance alongside abnormal mitochondrial morphology in gametocytes. This is the first study that explores the direct role of the PfCIII in gametogenesis via genetic disruption, paving the way for a better understanding of the role of mETC in the complex life cycle of these important parasites and providing further support for the focus of antimalarial drug development on this pathway. Full article
(This article belongs to the Special Issue Advances in Therapeutics against Eukaryotic Pathogens)
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17 pages, 3873 KiB  
Article
Effect of Hydroxyurea on Morphology, Proliferation, and Protein Expression on Taenia crassiceps WFU Strain
by Diana G. Rios-Valencia, Karel Estrada, Arturo Calderón-Gallegos, Rocío Tirado-Mendoza, Raúl J. Bobes, Juan P. Laclette and Margarita Cabrera-Bravo
Int. J. Mol. Sci. 2024, 25(11), 6061; https://doi.org/10.3390/ijms25116061 - 31 May 2024
Viewed by 713
Abstract
Flatworms are known for their remarkable regenerative ability, one which depends on totipotent cells known as germinative cells in cestodes. Depletion of germinative cells with hydroxyurea (HU) affects the regeneration of the parasite. Here, we studied the reduction and recovery of germinative cells [...] Read more.
Flatworms are known for their remarkable regenerative ability, one which depends on totipotent cells known as germinative cells in cestodes. Depletion of germinative cells with hydroxyurea (HU) affects the regeneration of the parasite. Here, we studied the reduction and recovery of germinative cells in T. crassiceps cysticerci after HU treatment (25 mM and 40 mM of HU for 6 days) through in vitro assays. Viability and morphological changes were evaluated. The recovery of cysticerci’s mobility and morphology was evaluated at 3 and 6 days, after 6 days of treatment. The number of proliferative cells was evaluated using EdU. Our results show morphological changes in the size, shape, and number of evaginated cysticerci at the 40 mM dose. The mobility of cysticerci was lower after 6 days of HU treatment at both concentrations. On days 3 and 6 of recovery after 25 mM of HU treatment, a partial recovery of the proliferative cells was observed. Proteomic and Gene Ontology analyses identified modifications in protein groups related to DNA binding, DNA damage, glycolytic enzymes, cytoskeleton, skeletal muscle, and RNA binding. Full article
(This article belongs to the Special Issue Advances in Therapeutics against Eukaryotic Pathogens)
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17 pages, 3277 KiB  
Article
Discovery of Strong 3-Nitro-2-Phenyl-2H-Chromene Analogues as Antitrypanosomal Agents and Inhibitors of Trypanosoma cruzi Glucokinase
by Shane M. Carey, Destiny M. O’Neill, Garrett B. Conner, Julian Sherman, Ana Rodriguez and Edward L. D’Antonio
Int. J. Mol. Sci. 2024, 25(8), 4319; https://doi.org/10.3390/ijms25084319 - 13 Apr 2024
Viewed by 1428
Abstract
Chagas disease is one of the world’s neglected tropical diseases, caused by the human pathogenic protozoan parasite Trypanosoma cruzi. There is currently a lack of effective and tolerable clinically available therapeutics to treat this life-threatening illness and the discovery of modern alternative [...] Read more.
Chagas disease is one of the world’s neglected tropical diseases, caused by the human pathogenic protozoan parasite Trypanosoma cruzi. There is currently a lack of effective and tolerable clinically available therapeutics to treat this life-threatening illness and the discovery of modern alternative options is an urgent matter. T. cruzi glucokinase (TcGlcK) is a potential drug target because its product, d-glucose-6-phosphate, serves as a key metabolite in the pentose phosphate pathway, glycolysis, and gluconeogenesis. In 2019, we identified a novel cluster of TcGlcK inhibitors that also exhibited anti-T. cruzi efficacy called the 3-nitro-2-phenyl-2H-chromene analogues. This was achieved by performing a target-based high-throughput screening (HTS) campaign of 13,040 compounds. The selection criteria were based on first determining which compounds strongly inhibited TcGlcK in a primary screen, followed by establishing on-target confirmed hits from a confirmatory assay. Compounds that exhibited notable in vitro trypanocidal activity over the T. cruzi infective form (trypomastigotes and intracellular amastigotes) co-cultured in NIH-3T3 mammalian host cells, as well as having revealed low NIH-3T3 cytotoxicity, were further considered. Compounds GLK2-003 and GLK2-004 were determined to inhibit TcGlcK quite well with IC50 values of 6.1 µM and 4.8 µM, respectively. Illuminated by these findings, we herein screened a small compound library consisting of thirteen commercially available 3-nitro-2-phenyl-2H-chromene analogues, two of which were GLK2-003 and GLK2-004 (compounds 1 and 9, respectively). Twelve of these compounds had a one-point change from the chemical structure of GLK2-003. The analogues were run through a similar primary screening and confirmatory assay protocol to our previous HTS campaign. Subsequently, three in vitro biological assays were performed where compounds were screened against (a) T. cruzi (Tulahuen strain) infective form co-cultured within NIH-3T3 cells, (b) T. brucei brucei (427 strain) bloodstream form, and (c) NIH-3T3 host cells alone. We report on the TcGlcK inhibitor constant determinations, mode of enzyme inhibition, in vitro antitrypanosomal IC50 determinations, and an assessment of structure–activity relationships. Our results reveal that the 3-nitro-2-phenyl-2H-chromene scaffold holds promise and can be further optimized for both Chagas disease and human African trypanosomiasis early-stage drug discovery research. Full article
(This article belongs to the Special Issue Advances in Therapeutics against Eukaryotic Pathogens)
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Review

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12 pages, 979 KiB  
Review
Microscopic Menaces: The Impact of Mites on Human Health
by Christina Linn, Andrea O’Malley, Kriti Khatri, Elaine M. Wright, Dylan Sebagh, Miodrag Grbić, Krzysztof Kowal and Maksymilian Chruszcz
Int. J. Mol. Sci. 2024, 25(7), 3675; https://doi.org/10.3390/ijms25073675 - 26 Mar 2024
Viewed by 1824
Abstract
Mites are highly prevalent arthropods that infest diverse ecological niches globally. Approximately 55,000 species of mites have been identified but many more are yet to be discovered. Of the ones we do know about, most go unnoticed by humans and animals. However, there [...] Read more.
Mites are highly prevalent arthropods that infest diverse ecological niches globally. Approximately 55,000 species of mites have been identified but many more are yet to be discovered. Of the ones we do know about, most go unnoticed by humans and animals. However, there are several species from the Acariformes superorder that exert a significant impact on global human health. House dust mites are a major source of inhaled allergens, affecting 10–20% of the world’s population; storage mites also cause a significant allergy in susceptible individuals; chiggers are the sole vectors for the bacterium that causes scrub typhus; Demodex mites are part of the normal microfauna of humans and their pets, but under certain conditions populations grow out of control and affect the integrity of the integumentary system; and scabies mites cause one of the most common dermatological diseases worldwide. On the other hand, recent genome sequences of mites provide novel tools for mite control and the development of new biomaterial with applications in biomedicine. Despite the palpable disease burden, mites remain understudied in parasitological research. By better understanding mite biology and disease processes, researchers can identify new ways to diagnose, manage, and prevent common mite-induced afflictions. This knowledge can lead to improved clinical outcomes and reduced disease burden from these remarkably widespread yet understudied creatures. Full article
(This article belongs to the Special Issue Advances in Therapeutics against Eukaryotic Pathogens)
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