2. Academic Validation
  3. Lower micromolar activity of the antifungal imidazoles on the bacterial-type bifunctional aldehyde/alcohol dehydrogenase (AdhE) in Cryptosporidium parvum and in vitro efficacy against the zoonotic parasite

Lower micromolar activity of the antifungal imidazoles on the bacterial-type bifunctional aldehyde/alcohol dehydrogenase (AdhE) in Cryptosporidium parvum and in vitro efficacy against the zoonotic parasite

  • Int J Parasitol Drugs Drug Resist. 2024 Jun 6:25:100551. doi: 10.1016/j.ijpddr.2024.100551.
Haichuan Chen 1,  Dongqiang Wang 2,  Chenchen Wang 3,  Peng Jiang 4,  Mingxiao Liu 5,  Jigang Yin 6,  Yonglan Yu 7
Affiliations

Affiliations

  • 1 College of Veterinary Medicine, China Agricultural University, Haidian District, Beijing, 100193, China. Electronic address: haichuanchen123@163.com.
  • 2 State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, 130062, China. Electronic address: wdq19@mails.jlu.edu.cn.
  • 3 State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, 130062, China. Electronic address: wang2020126@126.com.
  • 4 State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, 130062, China. Electronic address: jiangpeng22@mails.jlu.edu.cn.
  • 5 State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, 130062, China. Electronic address: mxliu19@mails.jlu.edu.cn.
  • 6 State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, 130062, China. Electronic address: yinjg@jlu.edu.cn.
  • 7 College of Veterinary Medicine, China Agricultural University, Haidian District, Beijing, 100193, China. Electronic address: gaodifeihao@cau.edu.cn.
PMID: 38875756 DOI: 10.1016/j.ijpddr.2024.100551
Abstract

Cryptosporidium parvum is a waterborne and foodborne zoonotic protozoan Parasite, a causative agent of moderate to severe diarrheal diseases in humans and Animals. However, fully effective treatments are unavailable for medical and veterinary uses. There is a need to explore new drug targets for potential development of new therapeutics. Because C. parvum relies on anaerobic metabolism to produce ATP, fermentative Enzymes in this Parasite are attractive targets for exploration. In this study, we investigated the ethanol-fermentation in the Parasite and characterized the basic biochemical features of a bacterial-type bifunctional aldehyde/alcohol dehydrogenase, namely CpAdhE. We also screened 3892 chemical entries from three libraries and identified 14 compounds showing >50% inhibition on the Enzyme activity of CpAdhE. Intriguingly, Antifungal imidazoles and unsaturated fatty acids are the two major chemical groups among the top hits. We further characterized the inhibitory kinetics of selected imidazoles and unsaturated fatty acids on CpAdhE. These compounds displayed lower micromolar activities on CpAdhE (i.e., IC50 values ranging from 0.88 to 11.02 μM for imidazoles and 8.93 to 35.33 μM for unsaturated fatty acids). Finally, we evaluated the in vitro anti-cryptosporidial efficacies and cytotoxicity of three imidazoles (i.e., tioconazole, miconazole and isoconazole). The three Antifungal imidazoles exhibited lower micromolar efficacies against the growth of C. parvum in vitro (EC50 values ranging from 4.85 to 10.41 μM and selectivity indices ranging from 5.19 to 10.95). The results provide a proof-of-concept data to support that imidazoles are worth being further investigated for potential development of anti-cryptosporidial therapeutics.

Keywords

Alcohol dehydrogenase (ADH); Anti-cryptosporidial efficacy; Antifungal imidazoles; Cryptosporidium parvum; Drug screening; Drug target.

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