Anti-<i>Giardia</i> Drug Discovery: Current Status and Gut Feelings

Riches, Andrew G.; Hart, Christopher J; Trenholme, Katharine R.; Skinner‐Adams, Tina S.

doi:10.1021/acs.jmedchem.0c00910

Cited by 40 publications

(47 citation statements)

References 195 publications

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“…The screening for new giardicidal drugs is undoubtedly a priority, since drug resistance and treatment failures are increasing [22]. As GlADI is absent in the human host, this enzyme is an attractive target for drug design against giardiasis [23].…”

Section: Discussionmentioning

confidence: 99%

Multilevel Approach for the Treatment of Giardiasis by Targeting Arginine Deiminase

Fernández-Lainez

Mora

García-Torres

et al. 2021

IJMS

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Giardiasis represents a latent problem in public health due to the exceptionally pathogenic strategies of the parasite Giardia lamblia for evading the human immune system. Strains resistant to first-line drugs are also a challenge. Therefore, new antigiardial therapies are urgently needed. Here, we tested giardial arginine deiminase (GlADI) as a target against giardiasis. GlADI belongs to an essential pathway in Giardia for the synthesis of ATP, which is absent in humans. In silico docking with six thiol-reactive compounds was performed; four of which are approved drugs for humans. Recombinant GlADI was used in enzyme inhibition assays, and computational in silico predictions and spectroscopic studies were applied to follow the enzyme’s structural disturbance and identify possible effective drugs. Inhibition by modification of cysteines was corroborated using Ellman’s method. The efficacy of these drugs on parasite viability was assayed on Giardia trophozoites, along with the inhibition of the endogenous GlADI. The most potent drug against GlADI was assayed on Giardia encystment. The tested drugs inhibited the recombinant GlADI by modifying its cysteines and, potentially, by altering its 3D structure. Only rabeprazole and omeprazole decreased trophozoite survival by inhibiting endogenous GlADI, while rabeprazole also decreased the Giardia encystment rate. These findings demonstrate the potential of GlADI as a target against giardiasis.

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Section: Discussionmentioning

confidence: 99%

Multilevel Approach for the Treatment of Giardiasis by Targeting Arginine Deiminase

Fernández-Lainez

Mora

García-Torres

et al. 2021

IJMS

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“…Several compounds have been tested against Giardia infections in dogs as benzimidazoles, in particular fenbendazole, and metronidazole that poses activity against the parasite (23)(24)(25)(26)(27)(28). Other studies reported the efficacy of ronidazole, nitazoxanide, azithromycin, tinidazole, and ipronidazole and other drugs such as quinacrine, furazolidone, in reducing Giardia cysts shed by infected dogs (17,(29)(30)(31)(32). Another option recommended by the European Scientific Counsel Companion Animal Parasites (ESCAAP) is the combination of febantel (a prodrug metabolized in vivo to fenbendazole)/pyrantel/praziquantel at the standard deworming dose (15.0 mg/kg of febantel, 14.4 mg/kg pyrantel, 5.0 mg/kg praziquantel) repeated once daily for 3 days (33).…”

Section: Introductionmentioning

confidence: 99%

Effectiveness of Fenbendazole and Metronidazole Against Giardia Infection in Dogs Monitored for 50-Days in Home-Conditions

et al. 2021

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A field trial performed in-home conditions was conducted on 24 dogs naturally infected with Giardia, in order to compare the efficacy of fenbendazole and metronidazole. Animals were allocated in groups randomly in order to obtain two groups of 12 dogs each with similar parasitic loads of Giardia cysts: dogs in Group A were treated with fenbendazole (Panacur®, Intervet Italia Srl) administered at the dose of 50 mg/kg orally once a day for 5 consecutive days, dogs in Group B were treated with metronidazole (Flagyl®, Zambon Italia Srl) administered orally at the dose of 50 mg/kg, once a day for 5 consecutive days. All the dogs that were shedding Giardia cysts after the first treatment (Day 0) were retreated (either at Day 7 or at Day 14 or at Day 21) until a negative result was obtained with the same treatment. Additionally, all the dogs were re-examined at Day 50. All the dogs were tested for the presence of Giardia cysts using a fecal flotation method (FLOTAC). The percent efficacy of the treatments (A and B) was calculated at each sampling point (Days 7, 14, 21, and 50) as reduction in mean Giardia cysts. After the first therapy, on day 7, 4/12 (33.3%) dogs tested positive for Giardia cysts in the Group A and 5/12 (41.7%) in the Group B. Efficacies at (Days 7, 14, 21, and 50) of the treatments against Giardia infection were 80.9, 94, 100, and 97% in the Group A and 70.8, 99, 100, and 97.1% in the Group B. Statistically significant differences were not observed between the efficacy of Fenbendazole and Metronidazole against infection by G. duodenalis (P = 0.686). Molecular analysis revealed full homology (i.e., 100% with JN416550) with the canine specific assemblage D in six positive dogs. Different hypotheses might explain the re-appearance of the Giardia cysts in some dogs after treatment, e.g., re-infection from the home environment, the correct medication given by the owners, the diet, as well as treatment failure, but also biological issues related to the intermittent excretion of Giardia cysts.

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“…Last not least, next to the development and implementation of new therapeutic strategies, infection prevention should not be neglected. Therefore, studies on successful enforcement of adequate hygiene standards to reduce both the transmission of G. duodenalis and the infectious burden will remain an issue of relevance [ 169 ]. Further, due to the difficult-to-control resistance conditions including the risk of multidrug resistance in G. duodenalis [ 170 ], also vaccine development remains an ongoing issue for the control of giardiasis [ 171 ].…”

Section: Discussionmentioning

confidence: 99%

Antimicrobial resistance of the enteric protozoon Giardia duodenalis – A narrative review

Loderstädt

Frickmann

2021

EuJMI

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IntroductionAs therapy-refractory giardiasis is an emerging health issue, this review aimed at summarizing mechanisms of reduced antimicrobial susceptibility in Giardia duodenalis and strategies to overcome this problem.MethodsA narrative review on antimicrobial resistance in G. duodenalis was based upon a selective literature research.ResultsFailed therapeutic success has been observed for all standard therapies of giardiasis comprising nitroimidazoles like metronidazole or tinidazole as first line substances but also benznidazoles like albendazole and mebendazole, the nitrofuran furazolidone, the thiazolide nitazoxanide, and the aminoglycoside paromomycin. Multicausality of the resistance phenotypes has been described, with differentiated gene expression due to epigenetic and post-translational modifications playing a considerable bigger role than mutational base exchanges in the parasite DNA. Standardized resistance testing algorithms are not available and clinical evidence for salvage therapies is scarce in spite of research efforts targeting new giardicidal drugs.ConclusionIn case of therapeutic failure of first line nitroimidazoles, salvage strategies including various options for combination therapy exist in spite of limited evidence and lacking routine diagnostic-compatible assays for antimicrobial susceptibility testing in G. duodenalis. Sufficiently powered clinical and diagnostic studies are needed to overcome both the lacking evidence regarding salvage therapy and the diagnostic neglect of antimicrobial resistance.

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Anti-Giardia Drug Discovery: Current Status and Gut Feelings

Cited by 40 publications

References 195 publications

Multilevel Approach for the Treatment of Giardiasis by Targeting Arginine Deiminase

Multilevel Approach for the Treatment of Giardiasis by Targeting Arginine Deiminase

Effectiveness of Fenbendazole and Metronidazole Against Giardia Infection in Dogs Monitored for 50-Days in Home-Conditions

Antimicrobial resistance of the enteric protozoon Giardia duodenalis – A narrative review

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