ABSTRACT
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.
Subject(s)
Anti-Bacterial Agents/pharmacology , Carbohydrate Dehydrogenases/antagonists & inhibitors , Gram-Positive Bacteria/drug effects , Pyrazoles/pharmacology , Carbohydrate Dehydrogenases/chemistry , Carbohydrate Dehydrogenases/metabolism , Crystallography , Fluorescence , Microbial Sensitivity Tests , Peptidoglycan/biosynthesis , Protein BindingABSTRACT
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.
Subject(s)
Carboxylic Acids/chemical synthesis , Lactones/chemical synthesis , Streptococcus pneumoniae/metabolism , Anti-Bacterial Agents/pharmacology , Anti-Infective Agents/pharmacology , Cell Wall/drug effects , Cell Wall/metabolism , Drug Resistance, Bacterial , Enterococcus faecalis/metabolism , Inhibitory Concentration 50 , Methicillin/pharmacology , Microbial Sensitivity Tests , Models, Chemical , Penicillins/pharmacology , Staphylococcus aureus/metabolism , Vancomycin/pharmacologyABSTRACT
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.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Carrier Proteins/chemistry , Cell Cycle Proteins/chemistry , Escherichia coli Proteins/chemistry , Indoles/chemical synthesis , Piperidines/chemical synthesis , Anti-Bacterial Agents/pharmacology , Cell Division/drug effects , Combinatorial Chemistry Techniques , Escherichia coli/cytology , Escherichia coli/drug effects , Indoles/pharmacology , Inhibitory Concentration 50 , Piperidines/pharmacology , Protein Binding/drug effects , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Anti-Bacterial Agents/pharmacology , Carbamates/chemistry , Carbamates/pharmacology , Peptidoglycan/biosynthesis , Phenylthiazolylthiourea/analogs & derivatives , Phenylthiazolylthiourea/pharmacology , Cell Wall/drug effects , Cell Wall/enzymology , Enterococcus faecalis/drug effects , Enterococcus faecalis/enzymology , Escherichia coli/drug effects , Escherichia coli/enzymology , Microbial Sensitivity Tests , Staphylococcus/drug effects , Staphylococcus/enzymologyABSTRACT
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.
Subject(s)
Bacterial Proteins/metabolism , Carrier Proteins/metabolism , Cell Cycle Proteins/metabolism , Cytoskeletal Proteins/metabolism , Drug Design , Escherichia coli Proteins/metabolism , Indoles/chemistry , Indoles/pharmacology , Bacterial Proteins/antagonists & inhibitors , Bacterial Proteins/chemistry , Carrier Proteins/antagonists & inhibitors , Carrier Proteins/chemistry , Cell Cycle Proteins/antagonists & inhibitors , Cell Cycle Proteins/chemistry , Cytoskeletal Proteins/antagonists & inhibitors , Cytoskeletal Proteins/chemistry , Escherichia coli Proteins/antagonists & inhibitors , Escherichia coli Proteins/chemistry , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Protein Binding/drug effects , Protein Structure, Tertiary , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Minocycline/analogs & derivatives , Minocycline/pharmacology , Staphylococcus epidermidis/drug effects , Bacterial Adhesion , Biofilms , Colony Count, Microbial , Culture Media , Microbial Sensitivity Tests , Polysaccharides/metabolism , Staphylococcus epidermidis/growth & development , TigecyclineABSTRACT
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.
