RESUMO
CS-023 (RO4908463, formerly R-115685) is a novel 1beta-methylcarbapenem with 5-substituted pyrrolidin-3-ylthio groups, including an amidine moiety at the C-2 position. Its antibacterial activity was tested against 1,214 clinical isolates of 32 species and was compared with those of imipenem, meropenem, ceftazidime, ceftriaxone, ampicillin, amikacin, and levofloxacin. CS-023 exhibited a broad spectrum of activity against gram-positive and -negative aerobes and anaerobes, including methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis, penicillin-resistant Streptococcus pneumoniae (PRSP), beta-lactamase-negative ampicillin-resistant Haemophilus influenzae, and Pseudomonas aeruginosa. CS-023 showed the most potent activity among the compounds tested against P. aeruginosa and MRSA, with MICs at which 90% of isolates tested were inhibited of 4 microg/ml and 8 microg/ml, respectively. CS-023 was stable against hydrolysis by the beta-lactamases from Enterobacter cloacae and Proteus vulgaris. CS-023 also showed potent activity against extended-spectrum beta-lactamase-producing Escherichia coli. The in vivo efficacy of CS-023 was evaluated with a murine systemic infection model induced by 13 strains of gram-positive and -negative pathogens and a lung infection model induced by 2 strains of PRSP (serotypes 6 and 19). Against the systemic infections with PRSP, MRSA, and P. aeruginosa and the lung infections, the efficacy of CS-023 was comparable to those of imipenem/cilastatin and vancomycin (tested against lung infections only) and superior to those of meropenem, ceftriaxone, and ceftazidime (tested against P. aeruginosa infections only). These results suggest that CS-023 has potential for the treatment of nosocomial bacterial infections by gram-positive and -negative pathogens, including MRSA and P. aeruginosa.
Assuntos
Antibacterianos , Carbapenêmicos , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Bactérias Gram-Positivas/efeitos dos fármacos , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Animais , Antibacterianos/química , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Carbapenêmicos/química , Carbapenêmicos/farmacocinética , Carbapenêmicos/farmacologia , Carbapenêmicos/uso terapêutico , Modelos Animais de Doenças , Farmacorresistência Bacteriana , Infecções por Bactérias Gram-Negativas/microbiologia , Infecções por Bactérias Gram-Positivas/microbiologia , Humanos , Camundongos , Testes de Sensibilidade MicrobianaRESUMO
Capuramycin analogues with a variety of substituents in place of the azepan-2-one moiety were synthesized from A-500359E and were tested for their translocase I inhibitory activity and in vitro antimycobacterial activity. Phenyl-type moieties were found to be effective substituents for capuramycin analogues.
Assuntos
Aminoglicosídeos/síntese química , Aminoglicosídeos/farmacologia , Antibacterianos/síntese química , Antibacterianos/farmacologia , Azepinas/química , Azepinas/farmacologia , Aminoglicosídeos/química , Antibacterianos/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Concentração Inibidora 50 , Testes de Sensibilidade Microbiana , Mycobacterium/efeitos dos fármacos , Relação Estrutura-Atividade , Transferases/antagonistas & inibidoresRESUMO
Acylated derivatives of capuramycin and A-500359A were synthesized and tested for antimycobacterial activity. Compound 20 having a decanoyl group showed very potent activity.
Assuntos
Aminoglicosídeos/síntese química , Aminoglicosídeos/farmacologia , Antibacterianos/síntese química , Antibacterianos/farmacologia , Acilação , Aminoglicosídeos/química , Antibacterianos/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Concentração Inibidora 50 , Isomerismo , Testes de Sensibilidade Microbiana , Mycobacterium/efeitos dos fármacos , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Relação Estrutura-Atividade , Transferases/antagonistas & inibidoresRESUMO
Plaunotol, a cytoprotective anti-ulcer agent, has antibacterial activity against Helicobacter pylori. The purpose of the present study was to investigate the effect of plaunotol when combined with clarithromycin or amoxicillin against H. pylori. When combined with clarithromycin, plaunotol showed synergic activity against 11 of 14 strains, and additive activity against the other three strains, by chequerboard titration. When combined with amoxicillin, plaunotol showed additive activity against 10 of 14 strains. No antagonistic effects were seen against any of the strains tested. The interactions between plaunotol and either clarithromycin or amoxicillin were determined by time-kill assay against the Sydney Strain (strain SS1) of H. pylori. The combination of plaunotol with clarithromycin showed synergic activity and with amoxicillin showed additive activity. In a C57BL/6 mouse gastritis model infected with H. pylori SS1, the plaunotol-clarithromycin and plaunotol-amoxicillin combinations both exhibited synergic effects, which allowed the effective dose of clarithromycin to be reduced when co-administered with plaunotol. These results suggest that plaunotol may have a useful role in combination with anti-H. pylori drugs in the treatment of H. pylori-associated diseases.
