Parasitic Diarrheal Disease: Drug Development and Targets

View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Frontiers - Publisher Connector REVIEW published: 27 October 2015 doi: 10.3389/fmicb.2015.01183 Parasitic diarrheal disease: drug development and targets Amir Azam 1*, Mudasir N. Peerzada 1 and Kamal Ahmad 2 1 Medicinal Chemistry Laboratory, Department of Chemistry, Jamia Millia Islamia, New Delhi, India, 2 Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India Diarrhea is the manifestation of gastrointestinal infection and is one of the major causes of mortality and morbidity specifically among the children of less than 5 years age worldwide. Moreover, in recent years there has been a rise in the number of reports of intestinal infections continuously in the industrialized world. These are largely related to waterborne and food borne outbreaks. These occur by the pathogenesis of both prokaryotic and eukaryotic organisms like bacteria and parasites. The parasitic intestinal infection has remained mostly unexplored and under assessed in terms of therapeutic development. The lack of new drugs and the risk of resistance have led us to carry out this review on drug development for parasitic diarrheal diseases. The major focus has been depicted on commercially available drugs, currently synthesized active heterocyclic compounds and unique drug targets, that are vital for the existence and growth of the parasites and can be further exploited for the search of therapeutically active Edited by: anti-parasitic agents. Anjan Debnath, Keywords: diarrhea, causative parasitic agents, chemotherapy, drug targets, therapeutic developments University of California, San Diego, USA Reviewed by: Ximin Zeng, INTRODUCTION University of Tennessee, USA Sharon Lee Reed, Diarrhea is a symptom of an infection in the intestinal tract, which can be caused by variety of UC San Diego Health Sciences, USA bacterial, viral, and parasitic organisms. Infection spreads through contaminated food or drinking *Correspondence: water or from person to person as a result of poor hygiene. Diarrheal diseases is the second leading Amir Azam cause of death in children under 5 years and is responsible for killing around 760,000 children [email protected] every year (World Health Organization, 2013). The common symptoms include the frequent bowel movements, loose watery stool, incontinence, lower abdominal pain, or cramping and in severe Specialty section: cases it causes blood or flecks of mucus in the stool. The dreadful infection leads to the loss of This article was submitted to appetite and patient is more likely to suffer from loss of weight. There are a number of non- Antimicrobials, Resistance and infectious medical conditions that may cause diarrhea too. The inability in digesting dairy products Chemotherapy, which includes lactose intolerance, coeliac disease which is an intolerance of gluten in wheat and a section of the journal some other grains and pancreatic problems (cystic fibrosis) which interfere with production of Frontiers in Microbiology important digestive substances (Haque et al., 2003). Several agents that cause diarrhea include Received: 10 June 2015 viruses (rotavirus or Norwalk virus, enterovirus, or a hepatitis virus), bacteria (Shigella species, Accepted: 12 October 2015 Escherichia coli, and Campylobacter jejuni) and parasites (Giardia lamblia, Entamoeba histolytica, Published: 27 October 2015 and Cryptosporidium species; Shah et al., 2009). Diarrhea caused by parasites is unlike that of either Citation: bacterial or viral infections. For instance, Giardia has a slow onset of diarrhea and can be present for Azam A, Peerzada MN and Ahmad K (2015) Parasitic diarrheal disease: months, while most bacterial and viral infections are limited to 1–2 weeks (Petri, 2003). In addition, drug development and targets. parasites are eukaryotic, which makes them larger and more complex than either viruses or bacteria Front. Microbiol. 6:1183. and also more difficult to eradicate due to their similarity to the host. Though the infection is caused doi: 10.3389/fmicb.2015.01183 by a number of parasites which mainly include G. lamblia, E. histolytica, Cryptosporidium parvum, Frontiers in Microbiology | www.frontiersin.org 1 October 2015 | Volume 6 | Article 1183 Azam et al. Drug development for diarrheal disease Cyclospora cayetanensis, Isospora belli, Blastocystis hominis but et al., 2004). The β-tubulin subunit is the primary target of the enzyme immunoassays are only available for the testing of benzimidazole, where its predictive sensitive residues are Cys three parasites G. lamblia, E. histolytica, and C. parvum (Slack, 165, Phe 167, Glu 198, Phe 200, Arg 242, and Val 268 (Macdonald 2012). et al., 2004; Tremoulet et al., 2004). It has been also reported Many of the new drug targets are being discovered with that microtubule assembly gets inhibited due to the presence of much more ease as the genomic sequences of many parasitic hydrogen atom at the 1-position and a methoxycarbonylamino organisms are becoming available. This advancement has enabled group at the 2-position of the benzimidazole ring (Friedman researchers not only to identify new biochemical pathways and and Platzer, 1980). Fumagillin along with its analogs act on the gene families that can be short-listed as potential drug targets methionine aminopeptidase type 2(MetAP2) by non-competitive but also has significantly increased their basic understanding of inhibition, i.e., by irreversibly blocking the active site in E. parasites that cause some of the most severe diseases. Moreover, cuniculi and it seems to be the potent inhibitor (Molina et al., biochemical analysis and genome sequencing both have helped 2002). Analysis of EcMetAP2 demonstrated conservation of in identifying potential targets, enzymes, transporters, and the key residues associated with the active site of this class metabolites that are distinct in parasites and their mammalian of enzymes including Asp251, Asp262, His331, Glu364, and host (Loftus et al., 2005). As a consequence one can design even Glu459 (involved in coordination of metal binding); His231 better and safer effective drugs that can be used in future to (to which fumagillin covalently binds); and Phe219, Leu328, combat the disease caused by the organism. The heterocyclic Ile338, His339, Asp378, Tyr444, Leu447 (involved in binding compounds with different modifications have been synthesized substrates into the active site; Upadhya et al., 2006). The and their biological evaluation have identified them to fight aspartic proteases are a family of protease enzymes that use the diarrhea causing parasites. In the following discussion some two highly conserved aspartic acid residues in the active site for of the most important parasites causing diarrhea, their drugs, catalytic cleavage of their peptide substrates (Pozio and Morales, important traced targets and the active heterocyclic compounds 2005). Ritonavir (12) and indinavir (13) drugs are inhibitors synthesized against them have been summarized. of aspartyl protease, used in the highly-active antiretroviral therapy cocktail, inhibited the growth of E. intestinalis in tissue MICROSPORIDIA culture due to intermolecular hydrogen bonding between -NH group of these drugs with aspartic acid residue (Menotti et al., Enterocytozoon bieneusi, Encephalitozoon cuniculi, and 2005; Pozio and Morales, 2005). The polyamine analogs are Encephalitozoon intestinalis are the reported species of important as they act by causing depletion of polyamines, due microsporidia which are the causative agents of chronic to excessive acetylation and excretion of intracellular amines, diarrhea predominantly in immunocompromised individuals followed by cytostasis, apoptosis and cell death (Bacchi et al., such as AIDS patients (Blanshard et al., 1992; Chokephaibulkit 2001). In sporoblasts of E. cuniculi, the chitin deacetylase et al., 2001; Goodgame, 2003). The diarrheal disease caused activity (EcCDA) is present in the inner part of the cell wall by microsporodia spp. is treated by drugs fumagilin (1) and tightly associated with the plasma membrane. This location was albendazole (2) (Goodgame, 2003; Agholi et al., 2013). The analyzed by biochemical and sequence data, and suggests a polyamine analogs, fumagillin-related compounds and analogs, role in cell-wall formation. Late sporogony was characterized nikkomycins (3), fluoroquinolones (4–9) and benzimidazole- by the thickening of the chitin-containing endospore, but related compounds are the active sources of new compounds the mechanism of chitin deposition is unknown. Since the against microsporidiosis. Fumagillin, a natural product (1) EcCDA enzyme is regularly distributed at the plasma membrane is an antibiotic and anti-angiogenic compound produced throughout sporogony, chitin may be produced all around by Aspergillus fumigatus and has been found potent against the cell (Brosson et al., 2005). The chitin is potent target of Encephalitozoon spp. and E. bieneusi in vitro (Bacchi and nikkomycins due to their deacetylation activity (Bacchi et al., Weiss, 2004). The antimicrosporidial activity of various 2001). The fluoroquinolones interact with E. cuniculi targets fluoroquinolones derivatives such as norfloxacin (4) and significantly with DNA topoisomerases, which are the enzymes ofloxacin (5) is more than gatifloxacin (6), lomefloxacin (7), that have evolved to solve the topological problems associated moxifloxacin (8), and nalidixic acid (9) and can be the effective with DNA

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