Structure-assisted discovery of an aminothiazole derivative as a lead molecule for inhibition of bacterial fatty-acid synthesis.

Structure-assisted discovery of an aminothiazole derivative as a lead molecule for inhibition of bacterial fatty-acid synthesis. Research Abstract Details 

Research Abstract Table of Contents

Jump to the:

Structure-assisted discovery of an aminothiazole derivative as a lead molecule for inhibition of bacterial fatty-acid synthesis. Abstract Text:

Pappenberger,Tanja Schulz-Gasch,Eric Kusznir,Francis ,Michael Hennig,Günter Pappenberger,Tanja Schulz-Gasch,Eric Kusznir,Francis Müller,Michael Hennig,

Fatty-acid synthesis in bacteria is of great interest as a target for the discovery of antibacterial compounds. The addition of a new acetyl moiety to the growing fatty-acid chain, an essential step in this process, is catalyzed by beta-ketoacyl-ACP synthase (KAS). It is inhibited by natural antibiotics such as cerulenin and thiolactomycin; however, these lack the requirements for optimal drug development. Structure-based biophysical screening revealed a novel synthetic small molecule, 2-phenylamino-4-methyl-5-acetylthiazole, that binds to Escherichia coli KAS I with a binding constant of 25 microM as determined by fluorescence titration. A 1.35 A crystal structure of its complex with its target reveals noncovalent interactions with the active-site Cys163 and hydrophobic residues of the fatty-acid binding pocket. The active site is accessible through an open conformation of the Phe392 side chain and no conformational changes are induced at the active site upon ligand binding. This represents a novel binding mode that differs from thiolactomycin or cerulenin interaction. The structural information on the protein-ligand interaction offers strategies for further optimization of this low-molecular-weight compound.

Structure-assisted discovery of an aminothiazole derivative as a lead molecule for inhibition of bacterial fatty-acid synthesis. Publishing Authors By Initials

G Pappenberger,T Schulz-Gasch,E Kusznir,F ,M Hennig,G Pappenberger,T Schulz-Gasch,E Kusznir,F Müller,M Hennig,

For similar abstracts research abstracts see: abstracts research

PUBMED ID PMID:

MEDLINE DATE:

Structure-assisted discovery of an aminothiazole derivative as a lead molecule for inhibition of bacterial fatty-acid synthesis. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Acta crystallographica. Section D, Biological crys

VOLUME: 63

Page Numbers: 1208-16

Journal Abbreviation: Acta Crystallogr. D Biol. Crys

ISSN: 0907-4449

DAY: 16

MONTH: 11

YEAR: 2007

Structure-assisted discovery of an aminothiazole derivative as a lead molecule for inhibition of bacterial fatty-acid synthesis. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 9305878

Structure-assisted discovery of an aminothiazole derivative as a lead molecule for inhibition of bacterial fatty-acid synthesis. Keywords Mesh Terms:

KEYWORDS:

MESH TERMS:

Chemical & Substance for Abstract: Structure-assisted discovery of an aminothiazole derivative as a lead molecule for inhibition of bacterial fatty-acid synthesis. Information

Substance Name:

Registry Number:

Grant and Affiliation Information for Structure-assisted discovery of an aminothiazole derivative as a lead molecule for inhibition of bacterial fatty-acid synthesis.

AFFILIATION: F. Hoffmann-La Roche Ltd, Pharma Research Discovery, CH-4070 Basel, Switzerland.

Country: Denmark

AGENCY:

GRANT:

ACRONYM:

MEDLINETA: Acta Crystallogr D Biol Crysta

REFSOURCE:

DATABASENAME:

ACCESSION NUMBER:

Number Hits: 0

Structure-assisted discovery of an aminothiazole derivative as a lead molecule for inhibition of bacterial fatty-acid synthesis Related Publications

• Changing ratios of omega-6 to omega-3 fatty acids can differentially modulate polychlorinated biphenyl toxicity in endothelial cells.
• Chromatin rearrangements in development.
• Cortisol as an indicator of dopaminergic effects on nicotine craving.
• Dissecting non-canonical interactions in frameshift-stimulating mRNA pseudoknots.
• EVE (external variance estimation) increases statistical power for detecting differentially expressed genes.
• Enzymatic synthesis and 19F NMR studies of 2-fluoroadenine-substituted RNA.
• High prevalence of cytomegalovirus DNA in plasma samples of blood donors in connection with seroconversion.
• Inversion recovery prepared turbo spin echo sequences with reduced SAR using smooth transitions between pseudo steady states.
• Is there a Role for ACIOLs in Developing Countries?
• Kinetics of PME/Pi in pig kidneys during cold ischemia.
• PPARalpha Ligands Reduce PCB-Induced Endothelial Activation: Possible Interactions in Inflammation and Atherosclerosis.
• PlantDB - a versatile database for managing plant research.
• Protein structure and oligomerization are important for the formation of export-competent HIV-1 Rev-RRE complexes.
• Structure-assisted discovery of an aminothiazole derivative as a lead molecule for inhibition of bacterial fatty-acid synthesis.
• The diagnosis of carcinoma of the esophagus; the method of biopsy with the retrograde curette.
• The influence of gliomas and nonglial space-occupying lesions on blood-oxygen-level-dependent contrast enhancement.
• The role of caveolin-1 in PCB77-induced eNOS phosphorylation in human-derived endothelial cells.
• The role of frequency, phase and time for processing of amplitude modulated signals by grasshoppers.
• Tyramine fragment binding to BACE-1.
• Zinc deficiency alters lipid metabolism in LDL receptor deficient mice treated with rosiglitazone.
• [Anesthesia in obstetrics and gynecology (clinical experiences in 2,344 cases)]
• [Development of a magnetic urethral closure device--an animal experiment study]
• [Effect of aryl- and alkylpolyglycol ethers on monamine oxidase from pig liver and on the mon- and diamine oxidase content of kidneys of fetal and adult animals.]
• [Extraction of enzymes by alcohol-water mixtures.]
• [Ileus in the puerperium. (Case report)]
• [Not Available.]
• [Not Available.]
• [Physical and physiological principles of calculating vascular resistance in cardiovascular circulation]
• [Possibilities for early ambulation and long-term outcome of treatment of trochanteric fractures with the dynamic hip screw and gamma nail]
• [Surgical treatment of injuries of the lower cervical spine]