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Journal of Biomolecular Screening
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1087057108329452v1
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Article

Comparison of 3 Cytotoxicity Screening Assays and Their Application to the Selection of Novel Antibacterial Hits

Luka Peternel*, Miha Kotnik, Andrej Prezelj, and Uros Urleb

* To whom correspondence should be addressed. E-mail: luka.peternel{at}sandoz.com.


  Abstract
Cytotoxicity screening of new chemical entities in antibacterial drug discovery discerns between cytotoxic and antimicrobial activity, thus providing predictive evidence for selective toxicity. The objective of this study was to evaluate 3 cytotoxicity assays in identifying novel antibacterial hits with desired safety margins. The endpoints in assays comprised adenylate kinase (AK) release rate as an indicator of membrane rupture (ToxilightTM), intracellular adenosine triphosphate (CellTiter-GloTM), and reduction of resazurin (CellTiter-BlueTM) both as indicators of cell metabolic activity. In the CellTiter-GloTM and the CellTiter-BlueTM assays, 7 of 8 selected compounds showed cytotoxicity, whereas in the ToxilightTM assay, 3 of 8 compounds significantly reduced cell viability in the ChoK1 and the JurkatE6.1 cell line. The CellTiter-GloTM assay proved to be the most sensitive among the evaluated assays, and excellent Z' values were obtained in the 96-well plate (Z' > 0.83). The CellTiter-GloTM assay was clearly superior to the CellTiter-BlueTM and the ToxilightTM assay for the initial cytotoxicity screening. Moreover, the application of the CellTiter-GloTM assay to determine mammalian cell toxicity versus the antibacterial effect ratio contributed to early identification of antibacterial hits with desired safety margins. The chemical structures of these novel antibacterial hits are disclosed herein. (Journal of Biomolecular Screening XXXX:xx-xx)

First published on February 4, 2009, doi:10.1177/1087057108329452

Journal of Biomolecular Screening 2009;14:142.

A more recent version of this article appeared on February 1, 2009

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