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BIOLOGICAL SCIENCES / MICROBIOLOGY
Discovery of platencin, a dual FabF and FabH inhibitor with in vivo antibiotic properties

Jun Wang^*,, Srinivas Kodali^*, Sang Ho Lee^*, Andrew Galgoci^*, Ronald Painter^*, Karen Dorso^*, Fred Racine^*, Mary Motyl^*, Lorraine Hernandez^*, Elizabeth Tinney^*, Steven L. Colletti^*, Kithsiri Herath^*, Richard Cummings^*, Oscar Salazar, Ignacio González, Angela Basilio, Francisca Vicente, Olga Genilloud, Fernando Pelaez, Hiranthi Jayasuriya^*, Katherine Young^*, Doris F. Cully^*, and Sheo B. Singh^*,

*Merck Research Laboratories, Rahway, NJ 07065; and Centro de Investigación Básica, Merck Sharp & Dohme de España, S.A. Josefa Valcárcel 38, Madrid 28027, Spain

Edited by Arnold L. Demain, Drew University, Madison, NJ, and approved March 9, 2007 (received for review January 26, 2007)

Emergence of bacterial resistance is a major issue for all classes of antibiotics; therefore, the identification of new classes is critically needed. Recently we reported the discovery of platensimycin by screening natural product extracts using a target-based whole-cell strategy with antisense silencing technology in concert with cell free biochemical validations. Continued screening efforts led to the discovery of platencin, a novel natural product that is chemically and biologically related but different from platensimycin. Platencin exhibits a broad-spectrum Gram-positive antibacterial activity through inhibition of fatty acid biosynthesis. It does not exhibit cross-resistance to key antibiotic resistant strains tested, including methicillin-resistant Staphylococcus aureus, vancomycin-intermediate S. aureus, and vancomycin-resistant Enterococci. Platencin shows potent in vivo efficacy without any observed toxicity. It targets two essential proteins, -ketoacyl-[acyl carrier protein (ACP)] synthase II (FabF) and III (FabH) with IC₅₀ values of 1.95 and 3.91 µg/ml, respectively, whereas platensimycin targets only FabF (IC₅₀ = 0.13 µg/ml) in S. aureus, emphasizing the fact that more antibiotics with novel structures and new modes of action can be discovered by using this antisense differential sensitivity whole-cell screening paradigm.

platensimycin | natural product | thiolactomycin | antisense | fatty acid synthesis

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0700746104/DC1.

To whom correspondence concerning biological matters should be addressed at: Merck & Co., P.O. Box 2000, R80W-250, Rahway, NJ 07065. E-mail: jun_wang2{at}merck.com

To whom correspondence concerning chemical matters should be addressed at: Merck & Co., P.O. Box 2000, R80Y-350, Rahway, NJ 07065. E-mail: sheo_singh{at}merck.com

© 2007 by The National Academy of Sciences of the USA

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