title: Discovery of platencin, a dual FabF and FabH inhibitor with in vivo antibiotic properties.
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.
authors: Merck Research Laboratories, Rahway, NJ 07065, USA. jun_wang2@merck.com
authors: Jun
authors: J
authors: Wang
authors: Srinivas
authors: S
authors: Kodali
authors: Sang Ho
authors: SH
authors: Lee
authors: Andrew
authors: A
authors: Galgoci
authors: Ronald
authors: R
authors: Painter
authors: Karen
authors: K
authors: Dorso
authors: Fred
authors: F
authors: Racine
authors: Mary
authors: M
authors: Motyl
authors: Lorraine
authors: L
authors: Hernandez
authors: Elizabeth
authors: E
authors: Tinney
authors: Steven L
authors: SL
authors: Colletti
authors: Kithsiri
authors: K
authors: Herath
authors: Richard
authors: R
authors: Cummings
authors: Oscar
authors: O
authors: Salazar
authors: Ignacio
authors: I
authors: González
authors: Angela
authors: A
authors: Basilio
authors: Francisca
authors: F
authors: Vicente
authors: Olga
authors: O
authors: Genilloud
authors: Fernando
authors: F
authors: Pelaez
authors: Hiranthi
authors: H
authors: Jayasuriya
authors: Katherine
authors: K
authors: Young
authors: Doris F
authors: DF
authors: Cully
authors: Sheo B
authors: SB
authors: Singh
mesh_terms: D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000627:Aminophenols / Q000737:chemistry / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D050296:Microbial Viability / Q000187:drug effects; D015394:Molecular Structure; D011083:Polycyclic Compounds / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000627:Aminophenols; D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D011083:Polycyclic Compounds; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase; C520340:platencin