Discovery of platencin, a dual FabF and FabH inhibitor with in vivo antibiotic properties

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 18; pp. 7612 - 7616
• Main Authors: Wang, Jun, Kodali, Srinivas, Lee, Sang Ho, Galgoci, Andrew, Painter, Ronald, Dorso, Karen, Racine, Fred, Motyl, Mary, Hernandez, Lorraine, Tinney, Elizabeth, Colletti, Steven L, Herath, Kithsiri, Cummings, Richard, Salazar, Oscar, González, Ignacio, Basilio, Angela, Vicente, Francisca, Genilloud, Olga, Pelaez, Fernando, Jayasuriya, Hiranthi, Young, Katherine, Cully, Doris F, Singh, Sheo B
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 01.05.2007; National Acad Sciences
• Subjects: 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase - antagonists & inhibitors; 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase - metabolism; Aminophenols - chemistry; Aminophenols - pharmacology; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterials; Antibiotics; Bacteria; Biological Sciences; Biosynthesis; Drug resistance; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes; Fatty acids; Inhibitory concentration 50; Microbial sensitivity tests; Microbial Viability - drug effects; Microbiology; Molecular Structure; Phospholipids; Polycyclic Compounds - chemistry; Polycyclic Compounds - pharmacology; Proteins; Quaternary ammonium compounds; Staphylococcus aureus
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0700746104

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, β-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.