Academic literature on the topic 'Antigiardial'

ABSTRACTGiardiasis is one of the most common causes of diarrheal disease worldwide. Treatment is primarily with 5-nitro antimicrobials, particularly metronidazole. Resistance to metronidazole has been described, and treatment failures can occur in up to 20% of cases, making development of alternative antigiardials an important goal. To this end, we have screened a chemical library of 746 approved human drugs and 164 additional bioactive compounds for activity againstGiardia lamblia. We identified 56 compounds that caused significant inhibition ofG. lambliagrowth and attachment. Of these, 15 were previously reported to have antigiardial activity, 20 were bioactive but not approved for human use, and 21 were drugs approved for human use for other indications. One notable compound of the last group was the antirheumatic drug auranofin. Further testing revealed that auranofin was active in the low (4 to 6)-micromolar range against a range of divergentG. lambliaisolates representing both human-pathogenic assemblages A and B. Most importantly, auranofin was active against multiple metronidazole-resistant strains. Mechanistically, auranofin blocked the activity of giardial thioredoxin oxidoreductase, a critical enzyme involved in maintaining normal protein function and combating oxidative damage, suggesting that this inhibition contributes to the antigiardial activity. Furthermore, auranofin was efficaciousin vivo, as it eradicated infection with differentG. lambliaisolates in different rodent models. These results indicate that the approved human drug auranofin could be developed as a novel agent in the armamentarium of antigiardial drugs, particularly against metronidazole-resistant strains.

The aim of this literature review is to compile data of heterocyclic antigiardial agents. The importance is to analyze the structural requirements for improved antigiardial activity, to overcome resistance and enhance the bioavailability of the compounds under study. Though, nitroimidazoles/ imidazoles and benzimidazoles are major classes, other heterocyclic scaffolds viz. oxoindolinylidene, dioxodihydroisobenzofuran-5-carboxamide, fluoroquinolone, thieno[2,3-b]pyridine- 5-carbonitrile, α-amino-phosphonate analogs of polyoxins, nitazoxanide benzologue, thiazole and triazolyl- quinolone chalcone also possess activity against Giardia species. Heterocyclic phytoconstituents are also included to have a deep idea of antigiardial activity of herbs possessing heterocyclic constituents.

ABSTRACT The protozoan pathogen Giardia is an important cause of parasitic diarrheal disease worldwide. It colonizes the lumen of the small intestine, suggesting that effective host defenses must act luminally. Immunoglobulin A (IgA) antibodies are presumed to be important for controlling Giardia infection, but direct evidence for this function is lacking. B-cell-independent effector mechanisms also exist and may be equally important for antigiardial host defense. To determine the importance of the immunoglobulin isotypes that are transported into the intestinal lumen, IgA and IgM, for antigiardial host defense, we infected gene-targeted mice lacking IgA-expressing B-cells, IgM-secreting B-cells, or all B-cells as controls with Giardia muris or Giardia lamblia GS/M-83-H7. We found that IgA-deficient mice could not eradicate either G. muris or G. lamblia infection, demonstrating that IgA is required for their clearance. Furthermore, although neither B-cell-deficient nor IgA-deficient mice could clear G. muris infections, IgA-deficient mice controlled infection significantly better than B-cell-deficient mice, suggesting the existence of B-cell-dependent but IgA-independent antigiardial defenses. In contrast, mice deficient for secreted IgM antibodies cleared G. muris infection normally, indicating that they have no unique functions in antigiardial host defense. These data, together with the finding that B-cell-deficient mice have some, albeit limited, residual capacity to control G. muris infection, show that IgA-dependent host defenses are central for eradicating Giardia spp. Moreover, B-cell-dependent but IgA-independent and B-cell-independent antigiardial host defenses exist but are less important for controlling infection.

ABSTRACTGiardia intestinalisis the most frequent protozoan agent of intestinal diseases worldwide. Though commonly regarded as an anaerobic pathogen, it preferentially colonizes the fairly oxygen-rich mucosa of the proximal small intestine. Therefore, when testing new potential antigiardial drugs, O2should be taken into account, since it also reduces the efficacy of metronidazole, the gold standard drug against giardiasis. In this study, 46 novel chalcones were synthesized by microwave-assisted Claisen-Schmidt condensation, purified, characterized by high-resolution mass spectrometry,1H and13C nuclear magnetic resonance, and infrared spectroscopy, and tested for their toxicity againstG. intestinalisunder standard anaerobic conditions. As a novel approach, compounds showing antigiardial activity under anaerobiosis were also assayed under microaerobic conditions, and their selectivity against parasitic cells was assessed in a counterscreen on human epithelial colorectal adenocarcinoma cells. Among the tested compounds, three [30(a), 31(e), and 33] were more effective in the presence of O2than under anaerobic conditions and killed the parasite 2 to 4 times more efficiently than metronidazole under anaerobiosis. Two of them [30(a) and 31(e)] proved to be selective against parasitic cells, thus representing potential candidates for the design of novel antigiardial drugs. This study highlights the importance of testing new potential antigiardial agents not only under anaerobic conditions but also at low, more physiological O2concentrations.

AbstractGiardia lamblia (G. lamblia) is the most widely known protozoan parasite that causes human gastrointestinal infection worldwide. Some natural compounds exhibited pivotal effects against different infectious diseases. In this research, the antigiardial activity and cytotoxicity of fungal chitosan, nano-chitosan, Rhamnus cathartica (R. cathartica) and emodin were evaluated in Balb/c mice. Genotyping of G. lamblia was assessed by PCR-RFLP technique. Different concentrations of mentioned compounds were used to check their antigiardial and cytotoxicity effects on human intestinal epithelial cells (HT-29) after 24, 48 and 72 h. The G. lamblia strain used in the current work was genotyped and revealed as an AII assemblage. All the concentration showed acceptable activity against G. lamblia cysts and trophozoites in comparison to the negative and positive controls (furazolidone and metronidazole) in vitro (P < 0.05). Giardia lamblia cysts were susceptible after treatment in all experiments in vivo in comparison to negative control (P < 0.05). Approximately, in most of the concentration, nano-chitosan and emodin were more effective than chitosan and R. cathartica, respectively (P < 0.05). The effects of exposure times in antigiardial and cytotoxicity effects were not statistically significant (P > 0.05). The maximum mortality rate (100%) was achieved at 100 and 50 µg kg−1 concentrations after 48 and 72 h of exposure time, respectively. Our results provide significant information about the new antigiardial agent and proposed the nano-chitosan and emodin for the development of new drugs against G. lamblia in the future.

Infectious diseases are one of the leading causes of morbidity and mortality worldwide. Diseases caused by single-celled organisms, such as bacteria and protista, cause billions of infections per year. One of the leading weapons in the fight against infectious diseases are antimicrobials. However, the efficacy of antimicrobials is decreasing as the development of antimicrobial resistance increases. At the same time as increasing levels of resistance are observed there is a lack of new antimicrobial agents entering the market and many big pharmaceutical companies have suspended antimicrobial drug discovery programs as financial return is small. Due to the lack of novel treatments for infectious diseases and increasing treatment failures it is essential that new chemical entities are explored to fill this gap. In this thesis a novel library of compounds based on the structure of robenidine, an approved antimicrobial used to prevent coccidiosis in chickens and rabbits, was investigated as potential antimicrobial agents. Initial experiments focussed on the antibacterial activity of the library against representative pathogenic bacteria. Activity was assessed according to CLSI guidelines. The spectrum of activity of the majority of analogues investigated was limited to Gram-positive bacteria, with promising MICs as low as 1.3 μM. However, through the use of outer-membrane permeabilising agents and spheroplast induction, it was discovered that the target site of robenidine and some of the related analogues was also present in Gram-negative organisms. This led to the development of a small subset of analogues which demonstrated intrinsic activity against the Gram-negative pathogens Escherichia coli and Pseudomonas aeruginosa with MICs as low as 52 μM. Furthermore, kill kinetic studies revealed that robenidine and related analogues had a bactericidal mechanism of action. The next series of experiments focussed on the characterisation of the antiparasitic activity of the library against the protists Trypanosoma brucei, Leishmania donovani and Giardia duodenalis. Several of the analogues demonstrated activity against these parasites with some promising results against Leishmania donovani including a small number of analogues with selectivity indices (SI) for the parasite above 20 (an SI of >10 is considered selective). In addition, activity against G. duodenalis was also promising (IC50 <1 μM). In total 121 analogues were tested against G. duodenalis with 13 being selective for Giardia with no antibacterial activity and limited, if any, toxicity towards mammalian cells. MICs for the most promising analogues were ≤ 2.8 μM. Electron microscopy studies to elucidate the mechanism or site of action of this class of antimicrobials against G. duodenalis demonstrated that the two most promising compounds both caused rapid disintegration of the cell membrane and the development of cyst-like structures, while one analogue also appeared to interfere with cell division. Finally, in order to test in vivo efficacy an animal model was effectively established in neonatal mice. In conclusion this thesis demonstrated for the first time the potential for this library of compounds to become therapeutic agents for a range of infectious diseases. In particular, the selective activity of several analogues for Giardia over other microorganisms and mammalian cells was demonstrated for the first time, highlighting the potential for this library of analogues. In addition, insight into the unique mechanism of action of a select group of compounds against G. duodenalis was demonstrated.
Thesis (Ph.D.) -- University of Adelaide, School of Animal and Veterinary Sciences, 2018