Ultrastructural Alterations of the Human Pathogen Giardia intestinalis after Drug Treatment
Abstract
:1. Introduction
Giardia Intestinalis and Its Biological Cycle
2. Morphology of the Two Stages in the Life Cycle of Giardia intestinalis as Observed Using Light and Electron Microscopy
2.1. Trophozoite
2.1.1. Nuclei
2.1.2. Flagella
2.1.3. Ventral Disc
2.1.4. Median Body
2.1.5. Peripheral Vesicles and the Endocytic Pathway
2.1.6. Endoplasmic Reticulum and Golgi Complex
2.1.7. Mitosomes
2.2. Cyst
3. Compounds Used in the Giardiasis Treatment and Their Effects on the Parasite (Table 1)
3.1. Metronidazole
3.2. Albendazole
3.3. Other Compounds
Drug | Mechanism | In Vitro Effects on the Parasite | Reference |
---|---|---|---|
Metronidazole | Reduced nitro group; forms toxic intermediate |
| [33,34] |
Albendazole | Bind to the beta-tubulin forming a “cap” at the plus end of microtubules |
| [44] |
Nitazoxanide | Inhibition of enzyme activity (PFOR, nitroreductase) |
| [48] |
Furazolidone | Reduced furazolidone; forms a toxic intermediate |
| [34] |
Paromomycin | Inhibit protein synthesis |
| [52] |
Quinacrine | Inhibit DNA synthesis |
| [49] |
4. Potential Drug Target
4.1. Giardia Cytoskeleton—Drugs Affecting Microtubules: Nocodazole, Colchicine, Taxol, Vinblastine, and Sulfonamide Oryzalin
4.2. Giardia Cytoskeleton—Drugs Affecting Actin: Cytochalasin D, Latrunculin A, Jasplakinolide
4.3. Giardia Organelles Affected by Drugs (Table 2)
4.4. Drugs Inducing Cell Death
4.5. Drugs Affecting Carbohydrates and Lipids Metabolism
4.6. G. intestinalis Kinases as Target Drug
4.7. Histone Acetylation as a Targeted Drug
4.8. G. intestinalis Redox Metabolism
Potential Target | Drug | In Vitro Effects on the Parasite | Reference |
---|---|---|---|
Cytoskeleton—Microtubules |
|
| [58,59,60,61] |
Cytoskeleton—Actin |
|
| [62,63] |
Organelles |
|
| [34,64] |
Cell death |
|
| [66,67] |
Carbohydrate metabolism |
|
| [70,71] |
Lipid metabolism |
|
| [73,74] |
Kinases |
|
| [76,77,78,79,80] |
Histone acetylation |
|
| [81,82,83,85,86] |
Redox metabolism |
|
| [34,90,91] |
5. New Compounds
5.1. Repositioning Compounds—Drugs Used for Other Diseases
- Robenidine is an anticoccidial drug first developed in the 1970s and now used regularly. In addition, it is added to the diet of various economically important animals, such as chickens and rabbits. Chemically, it is classified as a guanidine and has demonstrated inhibitory activity against the growth of G. intestinalis, with an IC50 in the range of 1 µm. Several analogs have been synthesized, and a library of 275 compounds has been developed and patented. Some of these derivatives, specifically compounds 45, 47, 48, and 49, have exhibited IC50 values below 10 µM. Additionally, certain derivatives have shown an ability to inhibit the adhesion of the trophozoite to the substrate. This action is particularly interesting as the pathogenicity of the protozoan largely relies on its capacity to adhere to the surface of intestinal epithelial cells [92,93].
- Secnidazole has been reported by Cheung et al. [94] as a treatment option for Giardiasis.
- As mentioned in the previous section, azidothymidine (AZT), an antiretroviral drug, has activity against Giardia, including strains resistant to metronidazole. In addition, AZT has shown inhibitory effects on cyst formation and, in experimental trials conducted on infected gerbils, reduced the number of trophozoites and cysts [80].
- As mentioned in the previous section, Auranofin, an antirheumatic compound, showed promising results against G. intestinalis [90].
- Mavelertinib exhibited substantial growth inhibition at a concentration of 5 µM. Furthermore, it demonstrated a significant effect in experimental Giardiasis, resulting in a notable reduction in parasite presence. This effect was evaluated through non-invasive imaging of whole mice infected with a Giardia green beetle strain [79].
- Steroid hormone 20-hydroxyecdysone showed efficacy against human Giardia infection. Furthermore, this drug exhibited superior effectiveness to metronidazole, as 4% of patients resisted the classical compound [99].
- Fumagillin, an anti-microsporidiosis drug, showed effects in a giardiasis mouse model. [100].
- Orlistat, a pancreatic lipase inhibitor used for treating obesity, demonstrated in vitro activity against G. intestinalis [101].
5.2. Repositioning Compounds—Compound Screening Library and Other Synthetic Drugs
- A library of 130 quinoxaline 1,4-di-N-oxides and certain derivatives within this library has demonstrated growth inhibitory activity with IC50 values below 10 µM. Notably, compounds 50, 51, 52, 53, and 54 were subjected to experimental infections in mice, and they exhibited superior activities compared to metronidazole and nitazoxanide [102,103].
- Triazoxins, a class of novel nucleoside analogs, have exhibited noteworthy activity against Giardia. Certain compounds within this group have demonstrated the ability to inhibit trophozoite growth with an IC50 of 5 µM. Additionally, other analogs have shown the capacity to inhibit trophozoite–cyst transformation in vitro [104].
- A screening of a substantial number (2451) of compounds from the Australian Scaffolds Library identified 40 hits against Giardia, exhibiting an IC50 of approximately 10 µM after 48 h of cultivation. Among these hits, three compounds demonstrated an IC50 of 1 µM, while CL9406 exhibited the lowest IC50 at 180 nM. Notably, the compound SN00797640 displayed potent activity against assemblages A, B, and metronidazole-resistant parasites [105]. However, further analysis of these compounds is required.
- Recently, Zheng et al. [106] reported the remarkable potency of a 3-nitroimidazo[1,2-b]pyridazine compound with an IC50 in the nanomolar (nM) range. This finding highlights the significance of this particular compound and warrants special attention.
- Due to the high glycolytic activity of Giardia, researchers have explored the testing of triose phosphate isomerase inhibitors. Compounds including benzothiazole, benzoxazole, benzimidazole, and sulphydryl derivatives have demonstrated meaningful activity in this regard [107].
- Interestingly, an inhibitor targeting the fused proteins glucose-6-phosphate dehydrogenase and 6-phosphogluconolactonase was observed with an IC50 of 10 µM [108].
- Benzopyrrolizidines have been successfully tested in Giardia cultures. Seventy-four compounds were evaluated, with several demonstrating an IC50 of 11 µM. These compounds induced notable morphological alterations in the parasite, including the loss of nuclei. Therefore, further detailed analysis of these c-mercapto benzimidazole compounds is warranted [109].
- Fernandez-Lainez et al. [110] reported the efficacy of compounds targeting arginine deiminase, an enzyme involved in a metabolic pathway associated with ATP synthesis, against Giardia.
- Gold nanoparticles, known for their broad-spectrum microbicidal activity, have demonstrated effectiveness against experimental Giardiasis in rats. These nanoparticles effectively inhibit the proliferation of trophozoites in the small intestine and the formation of cysts. The effects were evaluated using light and electron microscopy, revealing intestinal cell lesions’ recovery [111].
- The association of chitosan nanoparticles with metronidazole also exhibited significant efficacy in treating experimental Giardiasis in hamsters [112].
- In a recent study, Zoghroban et al. [113] demonstrated the significant efficacy of L-citrulline in controlling experimental Giardiasis in rats. The treatment resulted in reduced trophozoites in the intestinal mucosa and the complete elimination of cysts in the stool.
5.3. Natural Compounds
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Benchimol, M.; Gadelha, A.P.; de Souza, W. Ultrastructural Alterations of the Human Pathogen Giardia intestinalis after Drug Treatment. Pathogens 2023, 12, 810. https://doi.org/10.3390/pathogens12060810
Benchimol M, Gadelha AP, de Souza W. Ultrastructural Alterations of the Human Pathogen Giardia intestinalis after Drug Treatment. Pathogens. 2023; 12(6):810. https://doi.org/10.3390/pathogens12060810
Chicago/Turabian StyleBenchimol, Marlene, Ana Paula Gadelha, and Wanderley de Souza. 2023. "Ultrastructural Alterations of the Human Pathogen Giardia intestinalis after Drug Treatment" Pathogens 12, no. 6: 810. https://doi.org/10.3390/pathogens12060810