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