Current status and challenges in drug discovery against the globally important zoonotic cryptosporidiosis

The zoonotic cryptosporidiosis is globally distributed, one of the major diarrheal diseases in humans and animals. Cryptosporidium oocysts are also one of the major environmental concerns, making it a pathogen that fits well into the One Health concept. Despite its importance, fully effective drugs are not yet available. Anti-cryptosporidial drug discovery has historically faced many unusual challenges attributed to unique parasite biology and technical burdens. While significant progresses have been made recently, anti-cryptosporidial drug discovery still faces a major obstacle: identification of systemic drugs that can be absorbed by patients experiencing watery diarrhea and effectively pass through electron-dense (ED) band at the parasite-host cell interface to act on the epicellular parasite. There may be a need to develop an in vitro assay to effectively screen hits/leads for their capability to cross ED band. In the meantime, non-systemic drugs with strong mucoadhesive properties for extended gastrointestinal exposure may represent another direction in developing anti-cryptosporidial therapeutics. For developing both systemic and non-systemic drugs, a non-ruminant animal model exhibiting diarrheal symptoms suitable for routine evaluation of drug absorption and anti-cryptosporidial efficacy may be very helpful.