RÉSUMÉ
A series of 3,5-dioxopyrazolidines was identified as novel inhibitors of UDP-N-acetylenolpyruvylglucosamine reductase (MurB). Compounds 1 to 3, which are 1,2-bis(4-chlorophenyl)-3,5-dioxopyrazolidine-4-carboxamides, inhibited Escherichia coli MurB, Staphyloccocus aureus MurB, and E. coli MurA with 50% inhibitory concentrations (IC50s) in the range of 4.1 to 6.8 microM, 4.3 to 10.3 microM, and 6.8 to 29.4 microM, respectively. Compound 4, a C-4-unsubstituted 1,2-bis(3,4-dichlorophenyl)-3,5-dioxopyrazolidine, showed moderate inhibitory activity against E. coli MurB, S. aureus MurB, and E. coli MurC (IC50s, 24.5 to 35 microM). A fluorescence-binding assay indicated tight binding of compound 3 with E. coli MurB, giving a dissociation constant of 260 nM. Structural characterization of E. coli MurB was undertaken, and the crystal structure of a complex with compound 4 was obtained at 2.4 A resolution. The crystal structure indicated the binding of a compound at the active site of MurB and specific interactions with active-site residues and the bound flavin adenine dinucleotide cofactor. Peptidoglycan biosynthesis studies using a strain of Staphylococcus epidermidis revealed reduced peptidoglycan biosynthesis upon incubation with 3,5-dioxopyrazolidines, with IC50s of 0.39 to 11.1 microM. Antibacterial activity was observed for compounds 1 to 3 (MICs, 0.25 to 16 microg/ml) and 4 (MICs, 4 to 8 microg/ml) against gram-positive bacteria including methicillin-resistant S. aureus, vancomycin-resistant Enterococcus faecalis, and penicillin-resistant Streptococcus pneumoniae.
Sujet(s)
Antibactériens/pharmacologie , Carbohydrate dehydrogenases/antagonistes et inhibiteurs , Bactéries à Gram positif/effets des médicaments et des substances chimiques , Pyrazoles/pharmacologie , Carbohydrate dehydrogenases/composition chimique , Carbohydrate dehydrogenases/métabolisme , Cristallographie , Fluorescence , Tests de sensibilité microbienne , Peptidoglycane/biosynthèse , Liaison aux protéinesRÉSUMÉ
Pulvinones were synthesized (>180) in arrays and evaluated as inhibitors of early stage cell wall biosynthesis enzymes MurA-MurD. Several pulvinones inhibited Mur enzymes with IC(50)'s in the 1-10 microg/mL range and demonstrated antibacterial activity against Gram-positive bacteria including methicillin-resistant Staphyloccus aureus, vancomycin-resistant Enterococcus faecalis, and penicillin-resistant Streptococcus pneumoniae.
Sujet(s)
Acides carboxyliques/synthèse chimique , Lactones/synthèse chimique , Streptococcus pneumoniae/métabolisme , Antibactériens/pharmacologie , Anti-infectieux/pharmacologie , Paroi cellulaire/effets des médicaments et des substances chimiques , Paroi cellulaire/métabolisme , Résistance bactérienne aux médicaments , Enterococcus faecalis/métabolisme , Concentration inhibitrice 50 , Méticilline/pharmacologie , Tests de sensibilité microbienne , Modèles chimiques , Pénicillines/pharmacologie , Staphylococcus aureus/métabolisme , Vancomycine/pharmacologieRÉSUMÉ
The ZipA-FtsZ protein-protein interaction is a potential target for antibacterial therapy. The design and parallel synthesis of a combinatorial library of small molecules, which target the FtsZ binding area on ZipA are described. Compounds were demonstrated to bind to the FtsZ binding domain of ZipA by HSQC NMR and to inhibit cell division in a cell elongation assay.
Sujet(s)
Antibactériens/synthèse chimique , Protéines de transport/composition chimique , Protéines du cycle cellulaire/composition chimique , Protéines Escherichia coli/composition chimique , Indoles/synthèse chimique , Pipéridines/synthèse chimique , Antibactériens/pharmacologie , Division cellulaire/effets des médicaments et des substances chimiques , Techniques de chimie combinatoire , Escherichia coli/cytologie , Escherichia coli/effets des médicaments et des substances chimiques , Indoles/pharmacologie , Concentration inhibitrice 50 , Pipéridines/pharmacologie , Liaison aux protéines/effets des médicaments et des substances chimiques , Relation structure-activitéRÉSUMÉ
Over 50 phenyl thiazolyl urea and carbamate derivatives were synthesized for evaluation as new inhibitors of bacterial cell-wall biosynthesis. Many of them demonstrated good activity against MurA and MurB and gram-positive bacteria including MRSA, VRE and PRSP. 3,4-Difluorophenyl 5-cyanothiazolylurea (3p) with clog P of 2.64 demonstrated antibacterial activity against both gram-positive and gram-negative bacteria.
Sujet(s)
Antibactériens/pharmacologie , Carbamates/composition chimique , Carbamates/pharmacologie , Peptidoglycane/biosynthèse , Phényl-thiazolyl-thiourée/analogues et dérivés , Phényl-thiazolyl-thiourée/pharmacologie , Paroi cellulaire/effets des médicaments et des substances chimiques , Paroi cellulaire/enzymologie , Enterococcus faecalis/effets des médicaments et des substances chimiques , Enterococcus faecalis/enzymologie , Escherichia coli/effets des médicaments et des substances chimiques , Escherichia coli/enzymologie , Tests de sensibilité microbienne , Staphylococcus/effets des médicaments et des substances chimiques , Staphylococcus/enzymologieRÉSUMÉ
Structural features of two weak inhibitors of the ZipA-FtsZ protein-protein interaction which were found to bind to overlapping but different areas of the key binding site were combined in one new series of carboxybiphenyl-indoles with improved inhibitory activity.
Sujet(s)
Protéines bactériennes/métabolisme , Protéines de transport/métabolisme , Protéines du cycle cellulaire/métabolisme , Protéines du cytosquelette/métabolisme , Conception de médicament , Protéines Escherichia coli/métabolisme , Indoles/composition chimique , Indoles/pharmacologie , Protéines bactériennes/antagonistes et inhibiteurs , Protéines bactériennes/composition chimique , Protéines de transport/antagonistes et inhibiteurs , Protéines de transport/composition chimique , Protéines du cycle cellulaire/antagonistes et inhibiteurs , Protéines du cycle cellulaire/composition chimique , Protéines du cytosquelette/antagonistes et inhibiteurs , Protéines du cytosquelette/composition chimique , Protéines Escherichia coli/antagonistes et inhibiteurs , Protéines Escherichia coli/composition chimique , Concentration inhibitrice 50 , Modèles moléculaires , Structure moléculaire , Liaison aux protéines/effets des médicaments et des substances chimiques , Structure tertiaire des protéines , Relation structure-activitéRÉSUMÉ
The activity of tigecycline against Staphylococcus epidermidis growing in an in vitro adherent-cell biofilm model was determined. Tigecycline minimum bactericidal concentrations (MBCs) ranged from 1 to 8 microg/ml for S. epidermidis growing in a biofilm of adherent cells, compared to MBCs of 0.12 to >32 microg/ml for freely growing cells. The killing activity of tigecycline against the adherent bacteria was at least fourfold better than that of vancomycin and daptomycin.
Sujet(s)
Minocycline/analogues et dérivés , Minocycline/pharmacologie , Staphylococcus epidermidis/effets des médicaments et des substances chimiques , Adhérence bactérienne , Biofilms , Numération de colonies microbiennes , Milieux de culture , Tests de sensibilité microbienne , Polyosides/métabolisme , Staphylococcus epidermidis/croissance et développement , TigecyclineRÉSUMÉ
Twenty-five 2-phenyl-5,6-dihydro-2H-thieno[3,2-c]pyrazol-3-ol derivatives were synthesized for evaluation as new inhibitors of bacterial cell wall biosynthesis. Many of them demonstrated good inhibitory activity against Staphylococcus aureus MurB, MurC and MurD enzymes in vitro and antimicrobial activity against gram-positive bacteria including MRSA, VRE and PRSP. However, when they were tested in the presence of 4% bovine serum albumin, the MIC values increased to greater than 128 microg/mL against PRSP. None of the compounds demonstrated activity against gram-negative bacteria at MIC <32 microg/mL.