详细记录  
题名:Platensimycin is a selective FabF inhibitor with potent antibiotic properties.
作者:Wang J, Soisson SM, ..., Cully D, Singh SB
来源:Nature 2006 May 18 441(7091):358-61 [abstract on PubMed]
URL :http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16710421&dopt=Abstract&holding=f1000,f1000m
日期:060930
摘要: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.

Exceptional
F1000 Factor 10.0
Confirmation
New Finding
Controversial
Selected by | Jean-Jacques Sanglier / Russell Hill / Liang Tong / Joern Piel / Xiayang Qiu
First evaluation 25 May 2006 | Latest evaluation 7 Jun 2006
Comments
Jean-Jacques Sanglier
University of Strasbourg & Cetek Corporation, France
MICROBIOLOGY

New Finding
These authors present the first discovery of platensimycin - a novel antibacterial agent produced by a strain of Streptomyces platensis that comprises two distinct structural elements connected by an amide bond. This natural product selectively inhibits cellular lipid synthesis, a unique mode of action, and shows in vivo efficacy. No cross-resistance was observed.

Evaluated 7 Jun 2006
How to cite this evaluation
Russell Hill
University of Maryland Biotechnology Institute, United States of America
MICROBIOLOGY

New Finding
Platensimycin is in a new class of antibiotics discovered from a reliable old source, the Streptomycetes, and has promising broad-spectrum activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. By combining traditional natural products screening approaches with elegant whole-cell and biochemical assays, this research group from Merck have made an important and potentially life-saving discovery with this compound that inhibits the beta-ketoacyl-(acyl carrier protein) synthase I/II in the bacterial synthetic pathway of fatty acids. Clearly, natural sources in general and the remarkably versatile actinomycetes in particular still have a lot to offer in terms of drug discovery. Although there are many obstacles ahead for platensimycin along the arduous road to approval as a new drug, platensimycin offers some hope against resistant pathogenic bacteria.

Evaluated 31 May 2006
How to cite this evaluation
Liang Tong
Columbia University, United States of America
STRUCTURAL BIOLOGY

New Finding
This paper reports the identification of platensimycin as a potent antibiotic that inhibits the acyl-enzyme intermediate of the FabF enzyme in bacterial fatty acid biosynthesis. The compound is a broad-spectrum Gram-positive antibiotic (Gram-negatives are insensitive, possibly due to active efflux pumping), and does not show cross-resistance to other antibiotic resistance strains. A conformational change in the enzyme upon acylation is required before platensimycin can bind. The compound is produced by Streptomyces platensis.

Evaluated 30 May 2006
How to cite this evaluation
Joern Piel
University of Bonn, Germany
CHEMICAL BIOLOGY

New Finding
This milestone paper in natural product research reports the discovery of platensimycin, a bacterial antibiotic that represents a novel structural class. The compound is one of the few known inhibitors of the condensing enzyme FabF involved in bacterial fatty acid biosynthesis and is active against a wide range of antibiotic-resistant bacteria. Platensimycin has been discovered among 250,000 extracts using an interesting antisense approach that combines the molecular precision of target-based screenings with the immediate pharmacological assessment power of whole cell assays. The antibiotic eradicated Staphylococcus aureus in mice but still awaits further testing.

Evaluated 30 May 2006
How to cite this evaluation
Xiayang Qiu
Pfizer Inc., United States of America
STRUCTURAL BIOLOGY

Confirmation
New Finding
Controversial
This paper reports the discovery and characterization of a new compound, platensimycin, that seems to have broad-spectrum Gram-positive antibiotic activity by binding to the catalytic apparatus of a known antibacterial target FabF. Prior efforts in screening FabF and related FabH only yielded compounds with poor ADME/PK properties or an incomplete spectrum. Further positive data on S. pneumoniae could dismiss the old perceptions and validate FabF and related enzymes as viable antibacterial targets.

Evaluated 25 May 2006

http://www.f1000biology.com/article/id/1032455/evaluation

================  评  论  部  分=================

重要性:
分类:(参照 Faculty of 1000 的分类体系)


评语:

评论密码:   返回前页  [全部]