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J. Biol. Chem., Vol. 278, Issue 45, 44424-44428, November 7, 2003

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Discovery of a Small Molecule That Inhibits Cell Division by Blocking FtsZ, a Novel Therapeutic Target of Antibiotics^*

Jun Wang, Andrew Galgoci, Srinivas Kodali, Kithsiri B. Herath, Hiranthi Jayasuriya, Karen Dorso, Francisca Vicente, Antonio González, Doris Cully, David Bramhill, and Sheo Singh

From the Department of Human and Animal Infectious Disease and Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065

The emergence of bacterial resistance to antibiotics is a major health problem and, therefore, it is critical to develop new antibiotics with novel modes of action. FtsZ, a tubulin-like GTPase, plays an essential role in bacterial cell division, and its homologs are present in almost all eubacteria and archaea. During cell division, FtsZ forms polymers in the presence of GTP that recruit other division proteins to make the cell division apparatus. Therefore, inhibition of FtsZ polymerization will prevent cells from dividing, leading to cell death. Using a fluorescent FtsZ polymerization assay, the screening of >100,000 extracts of microbial fermentation broths and plants followed by fractionation led to the identification of viriditoxin, which blocked FtsZ polymerization with an IC₅₀ of 8.2 µg/ml and concomitant GTPase inhibition with an IC₅₀ of 7.0 µg/ml. That the mode of antibacterial action of viriditoxin is via inhibition of FtsZ was confirmed by the observation of its effects on cell morphology, macromolecular synthesis, DNA-damage response, and increased minimum inhibitory concentration as a result of an increase in the expression of the FtsZ protein. Viriditoxin exhibited broad-spectrum antibacterial activity against clinically relevant Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci, without affecting the viability of eukaryotic cells.

Received for publication, July 15, 2003 , and in revised form, August 29, 2003.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Merck & Co., Inc., P. O. Box 2000, R80Y-205, Rahway, NJ 07065. Tel.: 732-594-2776; Fax: 732-594-1399; E-mail: jun_wang2{at}merck.com.

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