RESUMO
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.
Assuntos
Antibacterianos/farmacologia , Desidrogenases de Carboidrato/antagonistas & inibidores , Bactérias Gram-Positivas/efeitos dos fármacos , Pirazóis/farmacologia , Desidrogenases de Carboidrato/química , Desidrogenases de Carboidrato/metabolismo , Cristalografia , Fluorescência , Testes de Sensibilidade Microbiana , Peptidoglicano/biossíntese , Ligação ProteicaRESUMO
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.
Assuntos
Ácidos Carboxílicos/síntese química , Lactonas/síntese química , Streptococcus pneumoniae/metabolismo , Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Parede Celular/efeitos dos fármacos , Parede Celular/metabolismo , Farmacorresistência Bacteriana , Enterococcus faecalis/metabolismo , Concentração Inibidora 50 , Meticilina/farmacologia , Testes de Sensibilidade Microbiana , Modelos Químicos , Penicilinas/farmacologia , Staphylococcus aureus/metabolismo , Vancomicina/farmacologiaRESUMO
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.
Assuntos
Antibacterianos/síntese química , Proteínas de Transporte/química , Proteínas de Ciclo Celular/química , Proteínas de Escherichia coli/química , Indóis/síntese química , Piperidinas/síntese química , Antibacterianos/farmacologia , Divisão Celular/efeitos dos fármacos , Técnicas de Química Combinatória , Escherichia coli/citologia , Escherichia coli/efeitos dos fármacos , Indóis/farmacologia , Concentração Inibidora 50 , Piperidinas/farmacologia , Ligação Proteica/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antibacterianos/farmacologia , Carbamatos/química , Carbamatos/farmacologia , Peptidoglicano/biossíntese , Feniltiazoliltioureia/análogos & derivados , Feniltiazoliltioureia/farmacologia , Parede Celular/efeitos dos fármacos , Parede Celular/enzimologia , Enterococcus faecalis/efeitos dos fármacos , Enterococcus faecalis/enzimologia , Escherichia coli/efeitos dos fármacos , Escherichia coli/enzimologia , Testes de Sensibilidade Microbiana , Staphylococcus/efeitos dos fármacos , Staphylococcus/enzimologiaRESUMO
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.
Assuntos
Proteínas de Bactérias/metabolismo , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas do Citoesqueleto/metabolismo , Desenho de Fármacos , Proteínas de Escherichia coli/metabolismo , Indóis/química , Indóis/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/química , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/química , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/química , Proteínas do Citoesqueleto/antagonistas & inibidores , Proteínas do Citoesqueleto/química , Proteínas de Escherichia coli/antagonistas & inibidores , Proteínas de Escherichia coli/química , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Estrutura Terciária de Proteína , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Minociclina/análogos & derivados , Minociclina/farmacologia , Staphylococcus epidermidis/efeitos dos fármacos , Aderência Bacteriana , Biofilmes , Contagem de Colônia Microbiana , Meios de Cultura , Testes de Sensibilidade Microbiana , Polissacarídeos/metabolismo , Staphylococcus epidermidis/crescimento & desenvolvimento , TigeciclinaRESUMO
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.