Platensimycin is a selective FabF inhibitor with potent antibiotic properties.
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.
Wang
Jun
J
Merck Research Laboratories, Rahway, New Jersey 07065, USA. jun_wang2@merck.com
Soisson
Stephen M
SM
Young
Katherine
K
Shoop
Wesley
W
Kodali
Srinivas
S
Galgoci
Andrew
A
Painter
Ronald
R
Parthasarathy
Gopalakrishnan
G
Tang
Yui S
YS
Cummings
Richard
R
Ha
Sookhee
S
Dorso
Karen
K
Motyl
Mary
M
Jayasuriya
Hiranthi
H
Ondeyka
John
J
Herath
Kithsiri
K
Zhang
Chaowei
C
Hernandez
Lorraine
L
Allocco
John
J
Basilio
Angela
A
Tormo
José R
JR
Genilloud
Olga
O
Vicente
Francisca
F
Pelaez
Fernando
F
Colwell
Lawrence
L
Lee
Sang Ho
SH
Michael
Bruce
B
Felcetto
Thomas
T
Gill
Charles
C
Silver
Lynn L
LL
Hermes
Jeffery D
JD
Bartizal
Ken
K
Barrett
John
J
Schmatz
Dennis
D
Becker
Joseph W
JW
Cully
Doris
D
Singh
Sheo B
SB
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
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