Novel lactate dehydrogenase inhibitors with in vivo efficacy against Cryptosporidium parvum

Kun Li, Sara M. Nader, Xuejin Zhang, Benjamin C. Ray, Chi Yong Kim, Aditi Das, William H. Witola

Research output: Contribution to journalArticle

Abstract

Cryptosporidium parvum is a highly prevalent zoonotic and anthroponotic protozoan parasite that causes a diarrheal syndrome in children and neonatal livestock, culminating in growth retardation and mortalities. Despite the high prevalence of C. parvum, there are no fully effective and safe drugs for treating infections, and there is no vaccine. We have previously reported that the bacterial-like C. parvum lactate dehydrogenase (CpLDH) enzyme is essential for survival, virulence and growth of C. parvum in vitro and in vivo. In the present study, we screened compound libraries and identified inhibitors against the enzymatic activity of recombinant CpLDH protein in vitro. We tested the inhibitors for anti-Cryptosporidium effect using in vitro infection assays of HCT-8 cells monolayers and identified compounds NSC158011 and NSC10447 that inhibited the proliferation of intracellular C. parvum in vitro, with IC50 values of 14.88 and 72.65 μM, respectively. At doses tolerable in mice, we found that both NSC158011 and NSC10447 consistently significantly reduced the shedding of C. parvum oocysts in infected immunocompromised mice’s feces, and prevented intestinal villous atrophy as well as mucosal erosion due to C. parvum. Together, our findings have unveiled promising anti-Cryptosporidium drug candidates that can be explored further for the development of the much needed novel therapeutic agents against C. parvum infections.

Original languageEnglish (US)
Article numbere1007953
JournalPLoS pathogens
Volume15
Issue number7
DOIs
StatePublished - Jul 2019

Fingerprint

Cryptosporidium parvum
L-Lactate Dehydrogenase
Cryptosporidium
Infection
Oocysts
Zoonoses
Livestock
Growth
Feces
Pharmaceutical Preparations
Inhibitory Concentration 50
Libraries
Atrophy
Virulence
Parasites
Vaccines

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Novel lactate dehydrogenase inhibitors with in vivo efficacy against Cryptosporidium parvum. / Li, Kun; Nader, Sara M.; Zhang, Xuejin; Ray, Benjamin C.; Kim, Chi Yong; Das, Aditi; Witola, William H.

In: PLoS pathogens, Vol. 15, No. 7, e1007953, 07.2019.

Research output: Contribution to journalArticle

Li, Kun ; Nader, Sara M. ; Zhang, Xuejin ; Ray, Benjamin C. ; Kim, Chi Yong ; Das, Aditi ; Witola, William H. / Novel lactate dehydrogenase inhibitors with in vivo efficacy against Cryptosporidium parvum. In: PLoS pathogens. 2019 ; Vol. 15, No. 7.
@article{b1634b3bb47040dba9a1393161e72a54,
title = "Novel lactate dehydrogenase inhibitors with in vivo efficacy against Cryptosporidium parvum",
abstract = "Cryptosporidium parvum is a highly prevalent zoonotic and anthroponotic protozoan parasite that causes a diarrheal syndrome in children and neonatal livestock, culminating in growth retardation and mortalities. Despite the high prevalence of C. parvum, there are no fully effective and safe drugs for treating infections, and there is no vaccine. We have previously reported that the bacterial-like C. parvum lactate dehydrogenase (CpLDH) enzyme is essential for survival, virulence and growth of C. parvum in vitro and in vivo. In the present study, we screened compound libraries and identified inhibitors against the enzymatic activity of recombinant CpLDH protein in vitro. We tested the inhibitors for anti-Cryptosporidium effect using in vitro infection assays of HCT-8 cells monolayers and identified compounds NSC158011 and NSC10447 that inhibited the proliferation of intracellular C. parvum in vitro, with IC50 values of 14.88 and 72.65 μM, respectively. At doses tolerable in mice, we found that both NSC158011 and NSC10447 consistently significantly reduced the shedding of C. parvum oocysts in infected immunocompromised mice’s feces, and prevented intestinal villous atrophy as well as mucosal erosion due to C. parvum. Together, our findings have unveiled promising anti-Cryptosporidium drug candidates that can be explored further for the development of the much needed novel therapeutic agents against C. parvum infections.",
author = "Kun Li and Nader, {Sara M.} and Xuejin Zhang and Ray, {Benjamin C.} and Kim, {Chi Yong} and Aditi Das and Witola, {William H.}",
year = "2019",
month = "7",
doi = "10.1371/journal.ppat.1007953",
language = "English (US)",
volume = "15",
journal = "PLoS Pathogens",
issn = "1553-7366",
publisher = "Public Library of Science",
number = "7",

}

TY - JOUR

T1 - Novel lactate dehydrogenase inhibitors with in vivo efficacy against Cryptosporidium parvum

AU - Li, Kun

AU - Nader, Sara M.

AU - Zhang, Xuejin

AU - Ray, Benjamin C.

AU - Kim, Chi Yong

AU - Das, Aditi

AU - Witola, William H.

PY - 2019/7

Y1 - 2019/7

N2 - Cryptosporidium parvum is a highly prevalent zoonotic and anthroponotic protozoan parasite that causes a diarrheal syndrome in children and neonatal livestock, culminating in growth retardation and mortalities. Despite the high prevalence of C. parvum, there are no fully effective and safe drugs for treating infections, and there is no vaccine. We have previously reported that the bacterial-like C. parvum lactate dehydrogenase (CpLDH) enzyme is essential for survival, virulence and growth of C. parvum in vitro and in vivo. In the present study, we screened compound libraries and identified inhibitors against the enzymatic activity of recombinant CpLDH protein in vitro. We tested the inhibitors for anti-Cryptosporidium effect using in vitro infection assays of HCT-8 cells monolayers and identified compounds NSC158011 and NSC10447 that inhibited the proliferation of intracellular C. parvum in vitro, with IC50 values of 14.88 and 72.65 μM, respectively. At doses tolerable in mice, we found that both NSC158011 and NSC10447 consistently significantly reduced the shedding of C. parvum oocysts in infected immunocompromised mice’s feces, and prevented intestinal villous atrophy as well as mucosal erosion due to C. parvum. Together, our findings have unveiled promising anti-Cryptosporidium drug candidates that can be explored further for the development of the much needed novel therapeutic agents against C. parvum infections.

AB - Cryptosporidium parvum is a highly prevalent zoonotic and anthroponotic protozoan parasite that causes a diarrheal syndrome in children and neonatal livestock, culminating in growth retardation and mortalities. Despite the high prevalence of C. parvum, there are no fully effective and safe drugs for treating infections, and there is no vaccine. We have previously reported that the bacterial-like C. parvum lactate dehydrogenase (CpLDH) enzyme is essential for survival, virulence and growth of C. parvum in vitro and in vivo. In the present study, we screened compound libraries and identified inhibitors against the enzymatic activity of recombinant CpLDH protein in vitro. We tested the inhibitors for anti-Cryptosporidium effect using in vitro infection assays of HCT-8 cells monolayers and identified compounds NSC158011 and NSC10447 that inhibited the proliferation of intracellular C. parvum in vitro, with IC50 values of 14.88 and 72.65 μM, respectively. At doses tolerable in mice, we found that both NSC158011 and NSC10447 consistently significantly reduced the shedding of C. parvum oocysts in infected immunocompromised mice’s feces, and prevented intestinal villous atrophy as well as mucosal erosion due to C. parvum. Together, our findings have unveiled promising anti-Cryptosporidium drug candidates that can be explored further for the development of the much needed novel therapeutic agents against C. parvum infections.

UR - http://www.scopus.com/inward/record.url?scp=85071222564&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85071222564&partnerID=8YFLogxK

U2 - 10.1371/journal.ppat.1007953

DO - 10.1371/journal.ppat.1007953

M3 - Article

C2 - 31356619

AN - SCOPUS:85071222564

VL - 15

JO - PLoS Pathogens

JF - PLoS Pathogens

SN - 1553-7366

IS - 7

M1 - e1007953

ER -