bekanamycin and Escherichia-coli-Infections

Components of fatty acid biosynthetic pathway have been identified as attractive targets for the development of new antibacterial agents. Compounds of series A (4a-4 g) and series B (5a-5 g) were synthesized by the formation of an amine bond between aromatic acid and 4-phenylthiazol-2-amine or 4-(4-bromophenyl)thiazol-2-amine. These thiazole derivatives have evaluated as potent FabH inhibitors. Nineteen compounds (4b-4h, 4 k, 4 l, 5a-5h, 5k, 5l) are reported for the first time. Most of the synthesized compounds exhibited antibacterial activity in the MTT assay. The MIC value of these compounds ranged from 1.56 μg/mL to 100 μg/mL. Moreover, the tested compounds also showed FabH inhibition ability with IC50 value ranging from 5.8 μM to 48.1 μM. The IC50 values are near the MIC values. Compound 5f has exhibited the best antibacterial and Escherichia coli FabH inhibitory activity. Docking simulation and the QSAR study was conducted for learning about binding mode and the relationship between structure and activity.

Topics: 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase; Acetyltransferases; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Drug Design; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Fatty Acid Synthase, Type II; Humans; Molecular Docking Simulation; Structure-Activity Relationship; Thiazoles

β-ketoacyl-acyl carrier protein synthase III (FabH) catalyzes the initial step of fatty acid biosynthesis via a type II fatty acid synthase in most bacteria. The important role of this essential enzyme combined with its unique structural features and ubiquitous occurrence in bacteria has made it an attractive new target for the development of new FabH inhibitors. We first used a structure-based approach to develop 24 new vinylogous carbamates (4a-15a, 4b-15b) that target FabH for the development of new antibiotics in this paper. Potent FabH inhibitory and selective anti- Gram-negative bacteria activities were observed in most of these vinylogous carbamates. Especially, compound 6a and 7a showed the most potent FabH inhibitory activity with IC₅₀ of 2.6 and 3.3 μM, respectively. Docking simulation was performed to position compound 6a into the Escherichia coli FabH active site and the possible binding conformation of compounds has been proposed. The biological data and molecular docking indicated that compounds 6a and 7a were potent inhibitors of E. coli FabH as antibiotics deserving further research.

Topics: 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase; Anti-Bacterial Agents; Carbamates; Drug Design; Enzyme Inhibitors; Escherichia coli; Escherichia coli Infections; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Models, Molecular; Structure-Activity Relationship

FabH, β-ketoacyl-acyl carrier protein (ACP) synthase III, is a particularly attractive target, since it is central to the initiation of fatty acid biosynthesis and is highly conserved among Gram-positive and Gram-negative bacteria. A series of o-hydroxybenzylamines 1-16 and its corresponding new urea derivatives 17-32 were synthesized and fully characterized by spectroscopic methods and elemental analysis. This new urea derivatives class demonstrates strong antibacterial activity. Escherichia coli FabH inhibitory assay and docking simulation indicated that the compounds 1-(5-bromo-2-hydroxybenzyl)-1-(4-fluorophenyl)-3-phenylurea (18) and 1-(5-bromo-2-hydroxybenzyl)-1-(4-chlorophenyl)-3-phenylurea (20) were potent inhibitors of E. coli FabH.

Topics: 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Drug Design; Enzyme Inhibitors; Escherichia coli; Escherichia coli Infections; Gram-Negative Bacteria; Humans; Microbial Sensitivity Tests; Models, Molecular; Protein Binding; Urea

Possible synergistic effects of the combination of EDTA-tromethamine (EDTA-Tris) and three antimicrobial agents (cephaloridine, kanendomycin and enrofloxacin) against resistant Gram-positive and Gram-negative bacteria are reported. Bacteria were isolated from eight cases of chronic otitis externa, five cases of chronic dermatitis and four cases of recurrent cystitis in dogs which had previously been treated with one of the three antibiotics without success. Animals exposed to EDTA-tromethamine plus the antibiotic recovered completely within 10 days, and were controlled clinically and bacteriologically for 180 days. Local irrigation with EDTA-tromethamine solution was well tolerated and no side effects were recorded.

Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Buffers; Cephaloridine; Cephalosporins; Cystitis; Dermatitis; Dog Diseases; Dogs; Drug Synergism; Edetic Acid; Enrofloxacin; Escherichia coli Infections; Female; Fluoroquinolones; Kanamycin; Male; Otitis; Proteus Infections; Proteus mirabilis; Pseudomonas Infections; Quinolones; Staphylococcal Infections; Time Factors; Tromethamine