RESUMO
Low-molecular-weight beta-sulfonyl- and beta-sulfinylhydroxamic acid derivatives have been synthesized and found to be potent inhibitors of Escherichia coli peptide deformylase (PDF). Most of the compounds synthesized and tested displayed antibacterial activities that cover several pathogens found in respiratory tract infections, including Chlamydia pneumoniae, Mycoplasma pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. The potential of these compounds as antibacterial agents is discussed with respect to selectivity, intracellular concentrations in bacteria, and potential for resistance development.
Assuntos
Amidoidrolases , Aminopeptidases/antagonistas & inibidores , Antibacterianos/síntese química , Inibidores Enzimáticos/síntese química , Ácidos Hidroxâmicos/síntese química , Antibacterianos/química , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Chlamydophila pneumoniae/efeitos dos fármacos , Cristalografia por Raios X , Resistência Microbiana a Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Escherichia coli/efeitos dos fármacos , Escherichia coli/enzimologia , Escherichia coli/metabolismo , Haemophilus influenzae/efeitos dos fármacos , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/metabolismo , Ácidos Hidroxâmicos/farmacologia , Modelos Moleculares , Moraxella catarrhalis/efeitos dos fármacos , Mycoplasma pneumoniae/efeitos dos fármacos , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Inibidores de Proteases/metabolismo , Inibidores de Proteases/farmacologia , Infecções Respiratórias/microbiologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Bridged monobactams are novel, potent, mechanism-based inhibitors of class C beta-lactamases, designed using X-ray crystal structures of the enzymes. They stabilize the acyl-enzyme intermediate by blocking access of water to the enzyme-inhibitor ester bond. Bridged monobactams are selective class C beta-lactamase inhibitors, with half-inhibition constants as low as 10 nM, and are less effective against class A and class B enzymes (half-inhibition constants > 100 microM) because of the different hydrolysis mechanisms in these classes of beta-lactamases. The stability of the acyl-enzyme complexes formed with class C beta-lactamases (half-lives up to 2 days were observed) enabled determination of their crystal structures. The conformation of the inhibitor moiety was close to that predicted by molecular modeling, confirming a simple reaction mechanism, unlike those of known beta-lactamase inhibitors such as clavulanic acid and penam sulfones, which involve secondary rearrangements. Synergy between the bridged monobactams and beta-lactamase-labile antibiotics could be observed when such combinations were tested against strains of Enterobacteriaceae that produce large amounts of class C beta-lactamases. The minimal inhibitory concentration of the antibiotic of more than 64 mg/L could be decreased to 0.25 mg/L in a 1:4 combination with the inhibitor.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Monobactamas/síntese química , Inibidores de beta-Lactamases , Acilação , Sítios de Ligação , Ceftriaxona/farmacologia , Cefalosporinas/farmacologia , Citrobacter freundii/efeitos dos fármacos , Citrobacter freundii/enzimologia , Sinergismo Farmacológico , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Escherichia coli/efeitos dos fármacos , Escherichia coli/enzimologia , Cinética , Modelos Moleculares , Conformação Molecular , Monobactamas/metabolismo , Monobactamas/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/enzimologia , Resistência beta-Lactâmica , beta-Lactamases/metabolismoRESUMO
A series of bridged monocyclic beta-lactams activated by various groups on the beta-lactam nitrogen (X = OCH2CO2H, OSO3H) has been synthesized and evaluated. Among them, the bridged sulfactams (X = OSO3H) were found to be effective beta-lactamase inhibitors. They inhibit both class A and class C beta-lactamases.
Assuntos
Acetatos/síntese química , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Ácidos Sulfônicos/síntese química , Inibidores de beta-Lactamases , beta-Lactamas/síntese química , Acetatos/química , Acetatos/farmacologia , Ceftriaxona/farmacologia , Cefalosporinas/farmacologia , Citrobacter freundii/efeitos dos fármacos , Citrobacter freundii/enzimologia , Sinergismo Farmacológico , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Escherichia coli/efeitos dos fármacos , Escherichia coli/enzimologia , Cinética , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/enzimologia , Ácidos Sulfônicos/química , Ácidos Sulfônicos/farmacologia , beta-Lactamas/química , beta-Lactamas/farmacologiaRESUMO
A general method for synthesis of 2 beta-alkenyl penam sulfones has been developed. The new compounds inhibited most of the common types of beta-lactamase. The level of activity depended very strongly on the nature of the substituent in the 2 beta-alkenyl group. The inhibited species formed with the beta-lactamase from Citrobacter freundii 1205 was sufficiently stable for X-ray crystallographic studies. These, together with UV absorption spectroscopy and studies of chemical degradation, suggested a novel reaction mechanism for the new inhibitors that might account for their broad spectrum of action. The (Z)-2 beta-acrylonitrile penam sulfone Ro 48-1220 was the most active inhibitor from this class of compound. The inhibitor enhanced the action of, for example, ceftriaxone against a broad selection of organisms producing beta-lactamases. The organisms included strains of Enterobacteriaceae that produce cephalosporinases, which is an exceptional activity for penam sulfones.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Lactamas , Inibidores de beta-Lactamases , beta-Lactamas/síntese química , Ceftriaxona/farmacologia , Citrobacter freundii/enzimologia , Ácido Clavulânico , Ácidos Clavulânicos/química , Ácidos Clavulânicos/metabolismo , Cristalografia por Raios X , Sinergismo Farmacológico , Enterobacter/efeitos dos fármacos , Enterobacter/enzimologia , Inibidores Enzimáticos/farmacologia , Modelos Moleculares , Estrutura Molecular , Pseudomonas/efeitos dos fármacos , Pseudomonas/enzimologia , Espectrofotometria Ultravioleta , beta-Lactamas/química , beta-Lactamas/farmacologiaRESUMO
Substituted 4-quinolone- (1, A = CH) and 1,8-naphthyrid-4-one- (1, A = N) 3-carboxylic acids are currently the only classes of clinically useful antibacterial agents exerting their activity by inhibiting the subunit A of DNA gyrase. Pyrimido[1,6-alpha]benzimidazoles 11 have been found to be a new class of inhibitors of this enzyme. The design, synthesis, and biological activity of these compounds are reported.