In vitro screening of the open source Pathogen Box identifies novel compounds with profound activities against Neospora caninum.

Müller, Joachim; Aguado Martinez, Adriana; Laleu, Benoît; Balmer, Vreni; Ritler, Dominic; Hemphill, Andrew (2017). In vitro screening of the open source Pathogen Box identifies novel compounds with profound activities against Neospora caninum. International journal for parasitology, 47(12), pp. 801-809. Elsevier 10.1016/j.ijpara.2017.06.002

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Neospora caninum is a major cause of abortion in cattle and represents an important veterinary health problem of great economic significance. The Medicines for Malaria Venture (MMV) Pathogen Box, an open-source collection of 400 compounds with proven anti-infective properties against a wide range of pathogens, was screened against a N. caninum beta-galactosidase reporter strain grown in human foreskin fibroblasts. A primary screening carried out at 1µM yielded 40 compounds that were effective against N. caninum tachyzoites. However, 30 of these compounds also affected the viability of the host cells. The 10 remaining compounds exhibited ICvalues between 4 and 43nM. Three compounds with ICvalues below 10nM, namely MMV676602, MMV688762 and MMV671636, were further characterized in vitro in more detail with respect to inhibition of invasion versus intracellular proliferation, and only MMV671636 had an impact on intracellular proliferation of tachyzoites. This was confirmed by transmission electron microscopy, showing that the primary target of MMV671636 was the mitochondrion. MMV671636 treatment of experimentally infected mice significantly reduced the number of animals with lung and brain infection, and these mice also exhibited a significantly reduced titer of antibodies directed against N. caninum antigens. Thus, MMV671636 is a promising starting point for the development of a future neosporosis therapy.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Research Foci > Host-Pathogen Interaction
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Parasitology
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)

UniBE Contributor:

Müller, Joachim; Aguado Martinez, Adriana; Balmer, Vreni; Ritler, Dominic and Hemphill, Andrew

Subjects:

600 Technology > 630 Agriculture
500 Science > 540 Chemistry
500 Science > 570 Life sciences; biology

ISSN:

0020-7519

Publisher:

Elsevier

Language:

English

Submitter:

Andrew Hemphill

Date Deposited:

17 May 2018 17:21

Last Modified:

16 Aug 2018 15:19

Publisher DOI:

10.1016/j.ijpara.2017.06.002

PubMed ID:

28751177

Uncontrolled Keywords:

Cerebral infection Drug development MMV Pathogen Box Mitochondrion Neospora caninum Neosporosis mouse model Real time PCR Transmission electron microscopy

BORIS DOI:

10.7892/boris.113112

URI:

https://boris.unibe.ch/id/eprint/113112

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