RESUMO
This paper describes the design and characterization of novel inhibitors of IleRS, whose binding affinity approaches the tightest reported for noncovalent inhibition. Compounds were designed from a binding model for the natural product pseudomonic acid-A (PS-A) together with a detailed understanding of the reaction cycle of IleRS and characterization of the mode of binding of the reaction intermediate IleAMP. The interactions of the compounds with IleRS were characterized by inhibition of aminoacylation of tRNA or PP(i)/ATP exchange at supersaturating substrate concentration and by transient kinetics and calorimetry methods. A detailed understanding of the interaction of a comprehensive series of compounds with IleRS allowed the identification of key features and hence the design of exquisitely potent inhibitors. Predictions based on these results have been recently supported by a docking model based on the crystal structure of IleRS with PS-A [Silvian, L. F., Wang J. M., and Steitz T. A. (1999) Science 285 1074-1077].
Assuntos
Antibacterianos/química , Inibidores Enzimáticos/síntese química , Isoleucina-tRNA Ligase/antagonistas & inibidores , Isoleucina-tRNA Ligase/química , Modelos Moleculares , Mupirocina/química , Antibacterianos/metabolismo , Sítios de Ligação , Varredura Diferencial de Calorimetria , Dicroísmo Circular , Inibidores Enzimáticos/metabolismo , Estabilidade Enzimática , Isoleucina/química , Isoleucina/metabolismo , Isoleucina-tRNA Ligase/metabolismo , Cinética , Modelos Químicos , Mupirocina/metabolismo , Espectrometria de Fluorescência , Staphylococcus aureus/enzimologia , Relação Estrutura-Atividade , TermodinâmicaRESUMO
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.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Bactérias/enzimologia , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Furanos/síntese química , Furanos/farmacologia , Tirosina-tRNA Ligase/antagonistas & inibidores , Compostos Bicíclicos Heterocíclicos com Pontes/química , Furanos/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Testes de Sensibilidade Microbiana , Estrutura MolecularRESUMO
A series of beta-diketone acrylate bioisosteres 4 of pseudomonic acid A 1 have been synthesized and evaluated for their ability to inhibit bacterial isoleucyl-tRNA synthetase and act as antibacterial agents. A number of analogues have excellent antibacterial activity. Selected examples were shown to afford good blood levels and to be effective in a murine infection model.
Assuntos
Cetonas/síntese química , Mupirocina/análogos & derivados , Mupirocina/síntese química , Animais , Antibacterianos/síntese química , Cetonas/sangue , Cetonas/farmacologia , Cinética , Masculino , Camundongos , Mupirocina/sangue , Mupirocina/farmacologia , Staphylococcus aureus/metabolismoRESUMO
The electronic requirements around the C1-C3 region of pseudomonic acid analogues were investigated. Synthetic routes were developed to access a range of compounds where the alpha, beta-unsaturated ester moiety had been replaced by a 5-membered ring heterocycle. The inhibition of isoleucyl tRNA synthetase from Staphylococcus aureus NCTC 6571 was determined as was the minimum inhibitory concentration (MIC) of the test compounds against that organism. Compounds possessing a region of electrostatic potential corresponding to that of the carbonyl group in the alpha, beta-unsaturated ester, and a low-energy unoccupied molecular orbital in the region corresponding to the double bond, were found to have IC50 values of 0.7-5.3 ng mL-1. However the MIC values of these compounds were in the range 2.0-8.0 micrograms mL-1, reflecting their poorer penetration into the bacterial cell.
Assuntos
Antibacterianos/síntese química , Inibidores Enzimáticos/síntese química , Isoleucina-tRNA Ligase/antagonistas & inibidores , Mupirocina/química , Antibacterianos/farmacologia , Inibidores Enzimáticos/farmacologia , Testes de Sensibilidade Microbiana , Modelos Moleculares , Mupirocina/análogos & derivados , Mupirocina/farmacologia , Espectrofotometria Infravermelho , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/enzimologia , Eletricidade Estática , Relação Estrutura-AtividadeRESUMO
A series of C-1 oxazole isosteres of pseudomonic acid A (mupirocin) bearing a nitroheterocycle have been synthesized, and significant differences in both spectrum of activity and potency were found between these derivatives and mupirocin. Additionally, the antibacterial potency of two members of this class of compounds against mupirocin-resistant staphylococci could not be accounted for solely by inhibition of the target enzyme isoleucyl-tRNA synthetase (IRS), indicating an additional mode of action. The most potent compound, the nitrofuran 3f (SB 205952), was the most electron affinic derivative prepared and was transformed by NAD(P)H-dependent bacterial reductases at a rate similar to that for nitrofurantoin. The second mode of action of this compound may therefore arise from its reduction to a species with cellular targets other than IRS. In in vivo studies, 3f was shown to be a very effective agent by both the subcutaneous and oral routes of administration.
Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Mupirocina/farmacologia , Mupirocina/análogos & derivados , Relação Estrutura-AtividadeRESUMO
The synthesis, antibacterial activities, murine pharmacokinetic and infection model data for a range of aryl and heteroaryl ketone derivatives of monic acid (2a) are reported. The best results were found for the 3-furyl and 2-methoxy thiazol-5-yl analogues.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Mupirocina/análogos & derivados , Mupirocina/química , Animais , Antibacterianos/farmacocinética , Humanos , Cetonas/química , Masculino , Camundongos , Camundongos Endogâmicos , Testes de Sensibilidade Microbiana , Mupirocina/farmacologia , Sepse/tratamento farmacológico , Infecções Estafilocócicas/tratamento farmacológico , Relação Estrutura-Atividade , Tiazóis/químicaRESUMO
Semisynthetic analogues of pseudomonic acid A have been prepared containing a heterocyclyl substituted oxazole. Derivatives in which the heterocycle was thiophene, furan, pyridine, or isoxazole showed good antibacterial potency and were further evaluated in vivo. Both pharmacokinetic parameters and oral activity against an experimental intraperitoneal sepsis were superior to results obtained from previously described pseudomonic acid A derivatives.
Assuntos
Antibacterianos/química , Mupirocina/análogos & derivados , Mupirocina/química , Oxazóis/síntese química , Animais , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Furanos/síntese química , Humanos , Isoxazóis/síntese química , Camundongos , Mupirocina/uso terapêutico , Oxazóis/farmacocinética , Oxazóis/uso terapêutico , Pirazóis/síntese química , Piridinas/síntese química , Sepse/tratamento farmacológico , Infecções Estafilocócicas/tratamento farmacológico , Tiazóis/síntese química , Tiofenos/síntese químicaRESUMO
Structure-activity relationships in a series of (5R)-6-triazolylmethylene penems with potent beta-lactamase inhibitory activity are described. In most cases, their in vitro synergistic activity with amoxycillin is superior to that of clavulanic acid, sulbactam and tazobactam (YTR 830). Against an Escherichia coli TEM-1 infection in mice, the compounds showed a broad range of potencies; an optimum polarity was found, however, which gave maximum potency.
Assuntos
Antibacterianos/síntese química , Triazóis/síntese química , Inibidores de beta-Lactamases , Amoxicilina/farmacologia , Animais , Antibacterianos/farmacologia , Sinergismo Farmacológico , Infecções por Escherichia coli/tratamento farmacológico , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Triazóis/farmacologiaRESUMO
Sodium (5RS)-Z-6-(substituted methylene)penem-3-carboxylates (3) are extremely potent inhibitors of bacterial beta-lactamases, but some members of this group of compounds are highly bound to human serum, while others are readily degraded by renal dehydropeptidase I enzyme. Consequently, the stability of a variety of 6-(substituted methylene)penems (3) to human kidney homogenate, their binding to human serum and their activity in a mouse infection model was investigated at an early stage, and were instrumental in the selection of the 1,2,3-triazolylmethylene derivatives (e.g. 3k) as a class of compounds worthy of further evaluation.
Assuntos
Antibacterianos/metabolismo , Proteínas Sanguíneas/metabolismo , Rim/metabolismo , Inibidores de beta-Lactamases , Animais , Antibacterianos/química , Antibacterianos/uso terapêutico , Estabilidade de Medicamentos , Infecções por Escherichia coli/tratamento farmacológico , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Conformação Molecular , Ligação Proteica , Espectrofotometria Infravermelho , Espectrofotometria Ultravioleta , beta-LactamasRESUMO
Sodium (5RS)-Z-6-(heterocyclylmethylene)penem-3-carboxylates (2) are a series of extremely potent inhibitors of bacterial beta-lactamases. A variety of 5-membered heteroaromatic derivatives have been prepared and structure-activity studies reveal a preferred substituent orientation. One of these derivatives, the 1-methyl-1,2,3-triazolyl compound (5m) is a more potent synergist of amoxycillin than clavulanic acid, sulbactam or tazobactam.
Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Inibidores de beta-Lactamases , Amoxicilina/farmacologia , Antibacterianos/química , Bactérias/enzimologia , Sinergismo Farmacológico , Conformação Molecular , Relação Estrutura-AtividadeRESUMO
A series of racemic 6-(substituted methylene)penems have been prepared. These compounds contain a 5-membered monoheteroaromatic ring at C-8. The antibacterial/synergistic and beta-lactamase inhibitory activities of both E- and Z-isomers and 2-substituted derivatives are compared.