Discovery of Novel Antigiardiasis Drug Candidates

Abstract

cGiardiasis is a severe intestinal parasitic disease caused by Giardia lamblia, which inflicts many people in poor regions and is the most common parasitic infection in the United States. Current standard care drugs are associated with undesirable side effects, treatment failures, and an increasing incidence of drug resistance. As follow-up to a high-throughput screening of an approved drug library, which identified compounds lethal to G. lamblia trophozoites, we have determined the minimum lethal concentrations of 28 drugs and advanced 10 of them to in vivo studies in mice. The results were compared to treatment with the standard care drug, metronidazole, in order to identify drugs with equal or better anti-Giardia activities. Three drugs, fumagillin, carbadox, and tioxidazole, were identified. These compounds were also potent against metronidazole-resistant human G. lamblia isolates (assemblages A and B), as determined in in vitro assays. Of these three compounds, fumagillin is currently an orphan drug used within the European Union to treat microsporidiosis in immunocompromised individuals, whereas carbadox and tioxidazole are used in veterinary medicine. A dose-dependent study of fumagillin in a giardiasis mouse model revealed that the effective dose of fumagillin was ϳ100-fold lower than the metronidazole dose. Therefore, fumagillin may be advanced to further studies as an alternative treatment for giardiasis when metronidazole fails.

Novel giardicidal compounds bearing proton pump inhibitor scaffold proceeding through triosephosphate isomerase inactivation

“…Owing to the rising of resistant strains of current drugs against G. lamblia , important efforts to search novel targets and design new anti-giardiasic drugs have been performed 20 , 27 , 28 . On this line, we and other research groups previously determined that omeprazole has anti-giardiasic activity 16 , 17 .…”

Proteomic and functional analyses reveal pleiotropic action of the anti-tumoral compound NBDHEX in Giardia duodenalis

“…Therefore, an implementation of the available anti-giardial arsenal with more potent, safe and well tolerated drugs are desirable. Novel classes of compounds, some already approved for unrelated human diseases treatment, are effective against Giardia (Tejman-Yarden et al., 2013, Hahn et al., 2013, Kulakova et al., 2014) and potential drug targets have been also identified (Reyes-Vivas et al., 2014, Debnath et al., 2014, Galkin et al., 2014). …”

The Critical Role of the Cytoskeleton in the Pathogenesis of Giardia

“…To combat resistance, new therapeutics are being explored that expand 5-nitroimidazole activity [53] or target Hsp90 [54]. Drugs such as Aurofin (an anti-rheumatic) [55] and fumagillin have been found to be effective against Giardia [56]. …”

“…Recent drug development strategies in Giardia have overwhelmingly focused on identifying new candidate anti-giardial drugs using high-throughput screening of large compound libraries. These screens have used both in vitro and in vivo assays that assess drug efficacy by quantifying parasite numbers or viability [56]. Candidate drug screening approaches have been used for decades to find drugs effective against Giardia .…”

“…Most screens measure viability [56, 66], but viability should not be the only measure of efficacy for a candidate drug. High-throughput candidate screens that only assay viability potentially overlook drugs that do not affect viability per se but do adversely affect infection.…”