Discovery of Platencin, a Dual FabF and FabH Inhibitor with in Vivo Antibiotic Properties

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2007 Apr 26

PMID 17456595

Citations 127

Authors

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 Gonzalez

Angela Basilio

Francisca Vicente

Olga Genilloud

Fernando Pelaez

Hiranthi Jayasuriya

Katherine Young

Doris F Cully

Sheo B Singh

Affiliations

Soon will be listed here.

Abstract

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, beta-ketoacyl-[acyl carrier protein (ACP)] synthase II (FabF) and III (FabH) with IC50 values of 1.95 and 3.91 microg/ml, respectively, whereas platensimycin targets only FabF (IC50 = 0.13 microg/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.

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