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JAC Advance Access originally published online on March 12, 2009
Journal of Antimicrobial Chemotherapy 2009 63(5):949-953; doi:10.1093/jac/dkp058
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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

Vinaxanthone, a new FabI inhibitor from Penicillium sp.

Chang Ji Zheng, Mi-Jin Sohn and Won-Gon Kim*

Korea Research Institute of Bioscience and Biotechnology, Yusong, Daejeon 305-806, Korea

Received 8 December 2008; returned 15 January 2009; revised 2 February 2009; accepted 3 February 2009

* Corresponding author. Tel: +82-42-860-4298; Fax: +82-42-8600-4595; E-mail: wgkim{at}kribb.re.kr

Objectives: Bacterial enoyl-ACP reductase (FabI) has been validated as a novel antibacterial target for tackling infections caused by multidrug-resistant pathogens. A few FabI inhibitors, however, are known. This study isolated a new FabI inhibitor from Penicillium sp.

Methods: A screening programme led to the selection of a Penicillium sp. producing a strong FabI-inhibitory metabolite. The chemical structure of the isolated FabI inhibitor was elucidated by mass spectrometry and nuclear magnetic resonance spectral data. The antibacterial target of the inhibitor was validated by overexpression assays.

Results: The isolated FabI inhibitor was elucidated to be vinaxanthone. It selectively inhibited Staphylococcus aureus FabI with an IC50 of 0.9 µM; it did not affect FabK, an enoyl-ACP reductase of Streptococcus pneumoniae. Consistent with its inhibition of FabI, the inhibitor prevented intracellular fatty acid synthesis while it did not affect protein biosynthesis. It also prevented the growth of S. aureus as well as methicillin-resistant S. aureus (MRSA) and quinolone-resistant S. aureus. Importantly, fabI-overexpressing S. aureus showed reduced susceptibility to the inhibitor compared with the wild-type strain, demonstrating that its antibacterial action is mediated by inhibition of FabI.

Conclusions: Vinaxanthone is a new FabI-directed antibacterial of natural origin that could have potential for further development as a new anti-MRSA agent.

Keywords: enoyl-ACP reductase , antibacterial , fatty acid synthesis , target validation , Staphylococcus aureus


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