Abstract
Giardiasis, a gastrointestinal disease caused by Giardia duodenalis, is currently treated mainly with nitroimidazoles, primarily metronidazole (MTZ). Treatment failure rates of up to 20 percent reflect the compelling need for alternative treatment options. Here, we investigated whether orlistat, a drug approved to treat obesity, represents a potential therapeutic agent against giardiasis. We compared the growth inhibitory effects of orlistat and MTZ on a long-term in vitro culture adapted G. duodenalis strain, WB-C6, and on a new isolate, 14-03/F7, from a patient refractory to MTZ treatment using a resazurin assay. The giardiacidal concentration of the drugs and their combined in vitro efficacy was determined by median-effect analysis. Morphological changes after treatment were analysed by light and electron microscopy. Orlistat inhibited the in vitro growth of G. duodenalis at low micromolar concentrations, with isolate 14-03/F7 (IC5024h = 2.8 µM) being more sensitive than WB-C6 (IC5024h = 6.2 µM). The effect was significantly more potent compared to MTZ (IC5024h = 4.3 µM and 11.0 µM, respectively) and led to specific undulated morphological alterations on the parasite surface. The giardiacidal concentration of orlistat was >14 µM for 14-03/F7 and >43 µM for WB-C6, respectively. Importantly, the combination of both drugs revealed no interaction on their inhibitory effects. We demonstrate that orlistat is a potent inhibitor of G. duodenalis growth in vitro and kills parasites at concentrations achievable in the gut by approved treatment regimens for obesity. We therefore propose to investigate orlistat in controlled clinical studies as a new drug in giardiasis.
Highlights
Giardiasis is caused by the protozoan parasite Giardia duodenalis
Satisfactory data sets were achieved with inoculum concentrations between 0.56103 and 104 parasites/well and an incubation time of 24 h followed by cultivation with resazurin for another 4 h
In the present study we show that the approved anti-obesity drug orlistat inhibits G. duodenalis growth in vitro
Summary
Giardiasis is caused by the protozoan parasite Giardia duodenalis G. intestinalis, G. lamblia) and is one of the most common parasitic diseases worldwide [1]. It has a significant impact on public health in both developing and developed countries and was included in the ‘neglected disease initiative’ of the WHO in 2004 [2]. The G. duodenalis species complex consists of eight main genotype groups (assemblages) that are morphologically identical but differ in host specificity. Assemblages A and B show the broadest host specificity and are the only assemblages that are pathogenic in humans. Association between specific genotypes and clinical symptoms have been inconclusive so far [6]
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