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JAC Advance Access originally published online on July 31, 2009
Journal of Antimicrobial Chemotherapy 2009 64(4):755-763; doi:10.1093/jac/dkp270
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© The Author 2009. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Identification of novel cell wall destabilizing antifungal compounds using a conditional Aspergillus nidulans protein kinase C mutant

Gabriel Mircus1, Shelly Hagag1, Emma Levdansky1, Haim Sharon1, Yona Shadkchan1, Itamar Shalit2 and Nir Osherov1,*

1 Department of Human Microbiology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel 2 Schneider Children's Medical Center of Israel, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel

Received 30 April 2009; returned 10 June 2009; revised 17 June 2009; accepted 5 July 2009

* Corresponding author: Tel: +972-3-640-9599; Fax: +972-3-640-9160; E-mail: nosherov{at}post.tau.ac.il

Objectives: Despite the need for novel drugs to combat fungal infections, antifungal drug discovery is currently limited by both the availability of suitable drug targets and assays to screen corresponding targets. The aim of this study was to screen a library of small chemical compounds to identify cell wall inhibitors using a conditional protein kinase C (PKC)-expressing strain of Aspergillus nidulans. This mutant is specifically susceptible to cell wall damaging compounds under PKC-repressive growth conditions.

Methods: The inhibitory effect of a library of small chemical compounds was examined in vitro using the conditional A. nidulans PKC strain and a panel of pathogenic fungal isolates. Microscopy was used to assess alterations to fungal ultrastructure following treatment.

Results: Three ‘hit’ compounds affecting cell wall integrity were identified from a screen of 5000 small chemical compounds. The most potent compound, CW-11, was further characterized and shown to specifically affect cell wall integrity. In clinical isolates of Aspergillus fumigatus, CW-11 induces morphological changes characteristic of damage to the cell wall, including wall thickening and rupturing. Analysis of the susceptibility of A. fumigatus and A. nidulans cell wall and signalling pathway mutants to CW-11 suggests that its mode of action differs from that of the antifungals caspofungin and voriconazole.

Conclusions: This work demonstrates the feasibility of using a conditional Aspergillus mutant to conduct a small-molecule library screen to identify novel ‘hit’ compounds affecting cell wall integrity.

Keywords: drug screen , compound library , cell wall integrity pathway


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