ABSTRACT
Optimisation of the left-hand-side aryl moiety of a file compound screening hit against Staphylococcus aureus methionyl tRNA synthetase led to the identification of a series of potent nanomolar inhibitors. The best compounds showed excellent antibacterial activity against staphylococcal and enterococcal pathogens, including strains resistant to clinical antibiotics.
Subject(s)
Anti-Infective Agents/chemical synthesis , Gram-Positive Bacteria/drug effects , Methionine-tRNA Ligase/antagonists & inhibitors , Drug Evaluation, Preclinical , Drug Resistance, Bacterial , Enterococcus/drug effects , Enterococcus/enzymology , Gram-Positive Bacteria/enzymology , Inhibitory Concentration 50 , Staphylococcus/drug effects , Staphylococcus/enzymology , Structure-Activity RelationshipABSTRACT
Carbocyclic analogues of the microbial metabolite SB-219383 have been synthesised and evaluated as inhibitors of bacterial tyrosyl tRNA synthetase. One compound showed highly potent and selective nanomolar inhibition.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemistry , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Furans/chemistry , Tyrosine-tRNA Ligase/antagonists & inhibitors , Tyrosine/analogs & derivatives , Tyrosine/chemistry , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Biochemistry/methods , Drug Design , Drug Evaluation, Preclinical , Staphylococcus aureus/enzymologyABSTRACT
SB-219383 and its analogues are a class of potent and specific inhibitors of bacterial tyrosyl-tRNA synthetases. Crystal structures of these inhibitors have been solved in complex with the tyrosyl-tRNA synthetase from Staphylococcus aureus, the bacterium that is largely responsible for hospital-acquired infections. The full-length enzyme yielded crystals that diffracted to 2.8 A resolution, but a truncated version of the enzyme allowed the resolution to be extended to 2.2 A. These inhibitors not only occupy the known substrate binding sites in unique ways, but also reveal a butyl binding pocket. It was reported that the Bacillus stearothermophilus TyrRS T51P mutant has much increased catalytic activity. The S. aureus enzyme happens to have a proline at position 51. Therefore, our structures may contribute to the understanding of the catalytic mechanism and provide the structural basis for designing novel antimicrobial agents.
Subject(s)
Enzyme Inhibitors/chemistry , Staphylococcus aureus/enzymology , Tyrosine-tRNA Ligase/chemistry , Amino Acid Sequence , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Crystallization , Crystallography, X-Ray , Dipeptides/chemistry , Dipeptides/pharmacology , Enzyme Inhibitors/pharmacology , Furans/chemistry , Furans/pharmacology , Models, Molecular , Molecular Sequence Data , Piperidines/chemistry , Piperidines/pharmacology , Protein Conformation , Sequence Homology, Amino Acid , Tyrosine-tRNA Ligase/antagonists & inhibitorsABSTRACT
A novel tyrosyl tRNA synthetase inhibitor, SB-219383, has been isolated from a Micromonospora sp. The structure of SB-219383 has been elucidated by a combination of derivatisation, spectroscopic and other analytical techniques and found to be N-(L-tyrosyl)-2-amino[1(S*),3(S*),4(S*),5(R*),8(R*)-2,4,5,8-tetrahydroxy -7-oxa-2-azabicyclo[3.2.1]oct-3-y1]acetic acid (1).
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemistry , Enzyme Inhibitors/chemistry , Furans/chemistry , Bridged Bicyclo Compounds, Heterocyclic/isolation & purification , Enzyme Inhibitors/isolation & purification , Enzyme Inhibitors/pharmacology , Furans/isolation & purification , Magnetic Resonance Spectroscopy , Micromonospora , Molecular Structure , Structure-Activity Relationship , Tyrosine-tRNA Ligase/antagonists & inhibitorsABSTRACT
Two novel isoleucyl tRNA synthetase inhibitors, SB-203207 and SB-203208 have been isolated from a Streptomyces sp. and found to be structurally related to altemicidin. Structures of SB-203207 and SB-203208 have been deduced by a combination of spectroscopic techniques, derivatisation, hydrolysis studies and found to be 4-(aminocarbonyl)-7-[[(2-amino-3-methylpentanoyl)aminosul phonyl]acetamido]-2,4a,5,6,7,7a-hexahydro-6-hydroxy-2-methyl-1H-2- pyrindine-7-carboxylic acid (1) and 4-(aminocarbonyl)-7-[[(2-amino-3-methyl pentanoyl)-aminosulphonyl]acetamido]-2,4a,5,6,7,7a-hexahydro-6-(2- amino-3-phenylbutanoyl oxy)-2-methyl-1H-2-pyrindine-7-carboxylic acid (2), respectively.
Subject(s)
Alkaloids/chemistry , Antibiotics, Antineoplastic/chemistry , Enzyme Inhibitors/chemistry , Indenes/chemistry , Pyridines , Sulfonamides/chemistry , Sulfur Compounds , Chromatography, High Pressure Liquid , Enzyme Inhibitors/pharmacology , Hydrolysis , Indenes/pharmacology , Isoleucine-tRNA Ligase/antagonists & inhibitors , Magnetic Resonance Spectroscopy , Molecular Structure , Streptomyces , Sulfonamides/pharmacologyABSTRACT
SB-219383 is a naturally occurring antibiotic, which acts by inhibition of tyrosyl tRNA synthetase. Semi-synthetic derivatives of SB-219383 were prepared with the objective of elucidating the key features required for inhibition of tyrosyl tRNA synthetase in order to improve the antibacterial activity. Some ester and amide derivatives as well as monocyclic analogues exhibited sub-nanomolar inhibitory activity against tyrosyl tRNA synthetase.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Bacteria/enzymology , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Furans/chemical synthesis , Furans/pharmacology , Tyrosine-tRNA Ligase/antagonists & inhibitors , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Furans/chemistry , Magnetic Resonance Spectroscopy , Mass Spectrometry , Microbial Sensitivity Tests , Molecular StructureABSTRACT
A potent inhibitor of seryl tRNA synthetase, designated SB-217452 has been isolated from Streptomyces sp. ATCC 700974. The fermentation, isolation, structure elucidation and some properties are described. SB-217452 showed inhibitory activity against both Staphylococcus aureus and rat seryl tRNA synthetases, with similar IC50 values of approximately 8 nM. The inhibitor is the serine linked nucleoside moiety of the antibiotic albomycin delta2. In contrast to albomycin delta2, SB-217452 showed only very weak antibacterial activity against a limited range of microorganisms. The compound has not been previously reported as a naturally occurring metabolite. In addition to SB-217452, albomycin delta2 Fe3+ complex and the novel Al3+ complex were isolated from the fermentation. These complexes had no seryl tRNA synthetase inhibitory activity.
Subject(s)
Enzyme Inhibitors/pharmacology , Pyrimidinones/pharmacology , Serine-tRNA Ligase/antagonists & inhibitors , Streptomyces/chemistry , Thiophenes/pharmacology , Animals , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/isolation & purification , Magnetic Resonance Spectroscopy , Molecular Structure , Pyrimidinones/chemistry , Pyrimidinones/isolation & purification , Rats , Spectrometry, Mass, Fast Atom Bombardment , Staphylococcus aureus/enzymology , Thiophenes/chemistry , Thiophenes/isolation & purificationABSTRACT
Tyrosyl aryl dipeptide inhibitors of S. aureus tyrosyl tRNA synthetase have been identified with IC50 values down to 0.5 microM. A crystal structure of the enzyme complexed to one of the inhibitors shows occupancy of the tyrosyl binding pocket coupled with inhibitor interactions to key catalytic residues.
Subject(s)
Dipeptides/chemistry , Enzyme Inhibitors/chemistry , Staphylococcus aureus/enzymology , Tyrosine-tRNA Ligase/chemistry , Binding Sites , Crystallography, X-Ray , Dipeptides/pharmacology , Enzyme Inhibitors/pharmacology , Glycine/analogs & derivatives , Models, Molecular , Molecular Structure , Protein Binding , Tyrosine/analogs & derivatives , Tyrosine-tRNA Ligase/antagonists & inhibitorsABSTRACT
Two novel glycopeptide antibiotics MM 55266 and MM 55268 containing fatty acid acyl functions, and of molecular formula C86H89N8O35Cl5 and C87H91N8O35Cl5, respectively, have been isolated and identified from a complex produced by Amycolatopsis sp. NCIB 40089. Fermentation conditions for their production, and methods for their isolation are described. Structures have been deduced by use of COSY and NOE NMR techniques and supported by chemical degradation studies. Both glycopeptides possessed good antibacterial activity against Gram-positive organisms.
Subject(s)
Actinomycetales/chemistry , Anti-Bacterial Agents , Anti-Bacterial Agents/isolation & purification , Glycopeptides/isolation & purification , Anti-Bacterial Agents/pharmacology , Glycopeptides/chemistry , Glycopeptides/pharmacology , Gram-Positive Bacteria/drug effects , Microbial Sensitivity Tests , Ristocetin/analogs & derivatives , Structure-Activity RelationshipABSTRACT
Structural modifications of the potassium channel activator cromakalim (1) are described in which the amide moiety at C-4 has been replaced by carboxamide and thiocarboxamide functions. Analogues in which the hydroxyl group at C-3 has been oxidized or removed are also disclosed. Such analogues display an interesting profile of smooth muscle relaxant activity in the guinea pig isolated trachea, not all of which appears to result from the opening of potassium channels, but few compounds retain useful in vivo activity. However, one compound in particular, 6-cyano-2,2-dimethyl-N-methyl-2H-1-benzopyran-4-thiocarboxamide (13) was shown to be a potent potassium channel activator in vitro and to provide prolonged protection to guinea pigs from the respiratory effects of inhaled histamine.
Subject(s)
Benzopyrans/chemistry , Benzopyrans/pharmacology , Bronchodilator Agents/pharmacology , Muscle Relaxation/drug effects , Pyrroles/chemistry , Thioamides/pharmacology , Trachea/drug effects , Animals , Benzopyrans/chemical synthesis , Bronchodilator Agents/chemical synthesis , Chemical Phenomena , Chemistry , Cromakalim , Guinea Pigs , Male , Molecular Structure , Muscle, Smooth/drug effects , Muscle, Smooth/physiology , Potassium Channels/drug effects , Potassium Channels/physiology , Pyrroles/pharmacology , Structure-Activity Relationship , Thioamides/chemical synthesis , Trachea/physiologyABSTRACT
The synthesis of a novel series of smooth muscle relaxants which have been shown to act via the opening or activation of potassium channels is described. Compounds have been evaluated for their ability to inhibit spontaneous tone in guinea pig isolated trachealis and structure-activity relationships are discussed. One compound in particular, 1,1-dimethyl-5-nitro-3-(2-pyridon-1-yl)indan-2-ol, (16) was identified as a potent relaxant of airways smooth muscle in vitro with IC50 = 0.15 microM and was found to significantly inhibit histamine-induced dyspnoea in conscious guinea pigs when given orally 30-45 min prior to challenge.
Subject(s)
Indans/chemical synthesis , Muscle Relaxation/drug effects , Muscle, Smooth/physiology , Parasympatholytics/chemical synthesis , Potassium Channels/drug effects , Amides/chemical synthesis , Amides/pharmacology , Animals , Benzopyrans/pharmacology , Bronchi/drug effects , Bronchi/physiology , Bronchodilator Agents , Chemical Phenomena , Chemistry , Cromakalim , Guinea Pigs , Indans/pharmacology , Male , Molecular Structure , Muscle, Smooth/drug effects , Parasympatholytics/pharmacology , Potassium Channels/physiology , Pyrroles/pharmacology , Stereoisomerism , Structure-Activity Relationship , Trachea/drug effects , Trachea/physiologyABSTRACT
A series of 4-amido-3,4-dihydro-2H-1-benzopyran-3-ols and 4-amido-2H-1-benzopyrans related to the potassium channel activator cromakalim have been prepared and evaluated for their relaxant activity in guinea pig isolated tracheal spirals. Several analogues show enhanced relaxant activity relative to cromakalim in this preparation and the rank order of potency for those substituents investigated at C-6 was CF3 greater than CN greater than C2H5 greater than aza greater than or equal to CH3. One compound, trans-3,4-dihydro-2,2-dimethyl-4-(2-oxopiperidin-1-yl)-7-(trifluor omethyl)-2H- 1-benzopyran-3-ol (24), was resolved into its two enantiomers and the activity was shown to reside essentially in the (+)-isomer, adding further support to the suggestion that the smooth muscle receptor for these potassium channel activators is stereoselective.