title: Platensimycin is a selective FabF inhibitor with potent antibiotic properties.
abstract: Bacterial infection remains a serious threat to human lives because of emerging resistance to existing antibiotics. Although the scientific community has avidly pursued the discovery of new antibiotics that interact with new targets, these efforts have met with limited success since the early 1960s. Here we report the discovery of platensimycin, a previously unknown class of antibiotics produced by Streptomyces platensis. Platensimycin demonstrates strong, broad-spectrum Gram-positive antibacterial activity by selectively inhibiting cellular lipid biosynthesis. We show that this anti-bacterial effect is exerted through the selective targeting of beta-ketoacyl-(acyl-carrier-protein (ACP)) synthase I/II (FabF/B) in the synthetic pathway of fatty acids. Direct binding assays show that platensimycin interacts specifically with the acyl-enzyme intermediate of the target protein, and X-ray crystallographic studies reveal that a specific conformational change that occurs on acylation must take place before the inhibitor can bind. Treatment with platensimycin eradicates Staphylococcus aureus infection in mice. Because of its unique mode of action, platensimycin shows no cross-resistance to other key antibiotic-resistant strains tested, including methicillin-resistant S. aureus, vancomycin-intermediate S. aureus and vancomycin-resistant enterococci. Platensimycin is the most potent inhibitor reported for the FabF/B condensing enzymes, and is the only inhibitor of these targets that shows broad-spectrum activity, in vivo efficacy and no observed toxicity.
authors.affiliation: Merck Research Laboratories, Rahway, New Jersey 07065, USA. jun_wang2@merck.com
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Soisson
authors.forename: Katherine
authors.initials: K
authors.lastname: Young
authors.forename: Wesley
authors.initials: W
authors.lastname: Shoop
authors.forename: Srinivas
authors.initials: S
authors.lastname: Kodali
authors.forename: Andrew
authors.initials: A
authors.lastname: Galgoci
authors.forename: Ronald
authors.initials: R
authors.lastname: Painter
authors.forename: Gopalakrishnan
authors.initials: G
authors.lastname: Parthasarathy
authors.forename: Yui S
authors.initials: YS
authors.lastname: Tang
authors.forename: Richard
authors.initials: R
authors.lastname: Cummings
authors.forename: Sookhee
authors.initials: S
authors.lastname: Ha
authors.forename: Karen
authors.initials: K
authors.lastname: Dorso
authors.forename: Mary
authors.initials: M
authors.lastname: Motyl
authors.forename: Hiranthi
authors.initials: H
authors.lastname: Jayasuriya
authors.forename: John
authors.initials: J
authors.lastname: Ondeyka
authors.forename: Kithsiri
authors.initials: K
authors.lastname: Herath
authors.forename: Chaowei
authors.initials: C
authors.lastname: Zhang
authors.forename: Lorraine
authors.initials: L
authors.lastname: Hernandez
authors.forename: John
authors.initials: J
authors.lastname: Allocco
authors.forename: Angela
authors.initials: A
authors.lastname: Basilio
authors.forename: José R
authors.initials: JR
authors.lastname: Tormo
authors.forename: Olga
authors.initials: O
authors.lastname: Genilloud
authors.forename: Francisca
authors.initials: F
authors.lastname: Vicente
authors.forename: Fernando
authors.initials: F
authors.lastname: Pelaez
authors.forename: Lawrence
authors.initials: L
authors.lastname: Colwell
authors.forename: Sang Ho
authors.initials: SH
authors.lastname: Lee
authors.forename: Bruce
authors.initials: B
authors.lastname: Michael
authors.forename: Thomas
authors.initials: T
authors.lastname: Felcetto
authors.forename: Charles
authors.initials: C
authors.lastname: Gill
authors.forename: Lynn L
authors.initials: LL
authors.lastname: Silver
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Hermes
authors.forename: Ken
authors.initials: K
authors.lastname: Bartizal
authors.forename: John
authors.initials: J
authors.lastname: Barrett
authors.forename: Dennis
authors.initials: D
authors.lastname: Schmatz
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Becker
authors.forename: Doris
authors.initials: D
authors.lastname: Cully
authors.forename: Sheo B
authors.initials: SB
authors.lastname: Singh
mesh_terms: D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D000081:Acetamides / Q000494:pharmacology / Q000633:toxicity; D000218:Adamantane; D062365:Aminobenzoates; D000617:Aminoglycosides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D000813:Anilides; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D001059:Apoproteins / Q000737:chemistry / Q000378:metabolism; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D000069349:Linezolid; D008055:Lipids / Q000096:biosynthesis; D051379:Mice; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D023303:Oxazolidinones / Q000494:pharmacology / Q000633:toxicity; D013302:Streptomyces / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D000081:Acetamides; D062365:Aminobenzoates; D000617:Aminoglycosides; D000813:Anilides; D000900:Anti-Bacterial Agents; D001059:Apoproteins; D001426:Bacterial Proteins; D008055:Lipids; D023303:Oxazolidinones; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase; D000069349:Linezolid; D000218:Adamantane; C510909:platensimycin