Journal Article

Amelioration of Cryptosporidium parvum Infection In Vitro and In Vivo by Targeting Parasite Fatty Acyl-Coenzyme A Synthetases

Xiang, Lixin, Guo, Fengguang, Mead, Jan R., Zhu, Guan, McNair, Nina N., Fritzler, Jason M., Rider, S. Dean, Zhang, Haili

2014

Overview

Background. Cryptosporidium is emerging as 1 of the 4 leading diarrheal pathogens in children in developing countries. Its infections in patients with AIDS can be fatal, whereas fully effective treatments are unavailable. The major goal of this study is to explore parasite fatty acyl-coenzyme A synthetase (ACS) as a novel drug target. Methods. A colorimetric assay was developed to evaluate biochemical features and inhibitory kinetics of Cryptosporidium parvum ACSs using recombinant proteins. Anticryptosporidial efficacies of the ACS inhibitor triacsin C were evaluated both in vitro and in vivo. Results. Cryptosporidium ACSs displayed substrate preference toward long-chain fatty acids. The activity of parasite ACSs could be specifically inhibited by triacsin C with the inhibition constant Ki in the nanomolar range. Triacsin C was highly effective against C. parvum growth in vitro (median inhibitory concentration, 136 nmol/L). Most importantly, triacsin C effectively reduced parasite oocyst production up to 88.1% with no apparent toxicity when administered to Cryptosporidium-infected interleukin 12 knockout mice at 8-15 mg/kg/d for 1 week. Conclusions. The findings of this study not only validated Cryptosporidium ACS (and related acyl-[acyl-carrierprotein]-ligases) as pharmacological targets but also indicate that triacsin C and analogues can be explored as potential new therapeutics against the virtually untreatable cryptosporidial infection in immunocompromised patients.

• Publisher: Oxford University Press
• Subject: Animals / Biochemistry / Biological and medical sciences / Cell Culture Techniques / Cloning, Organism / Coenzyme A Ligases - antagonists & inhibitors / Coenzyme A Ligases - metabolism / Cryptosporidiosis / Cryptosporidiosis - enzymology / Cryptosporidiosis - prevention & control / Cryptosporidium parvum - enzymology / Dosage / Enzyme Inhibitors - pharmacology / Enzymes / Fatty acids / Fundamental and applied biological sciences. Psychology / Gene expression / Human protozoal diseases / Humans / Infections / Infectious diseases / Major and Brief Reports / Medical sciences / Mice / Microbiology / Oocysts / Parasites / Parasitic diseases / Proteins / Protozoal diseases / Triazenes - pharmacology