RESUMO
Racemic 2,4-diaminopyrimidine dihydrophthalazine derivatives BAL0030543, BAL0030544, and BAL0030545 exhibited low in vitro MICs toward small, selected panels of Enterococcus faecalis, Enterococcus faecium, Streptococcus pneumoniae, Moraxella catarrhalis, and Mycobacterium avium, though the compounds were less active against Haemophilus influenzae. The constellation of dihydrofolate reductases (DHFRs) present in 20 enterococci and 40 staphylococci was analyzed and correlated with the antibacterial activities of the dihydrophthalazines and trimethoprim. DHFRs encoded by dfrB, dfrA (S1 isozyme), dfrE, and folA were susceptible to the dihydrophthalazines, whereas DHFRs encoded by dfrG (S3 isozyme) and dfrF were not. Studies with the separated enantiomers of BAL0030543, BAL0030544, and BAL0030545 revealed preferential inhibition of susceptible DHFRs by the (R)-enantiomers. BAL0030543, BAL0030544, and BAL0030545 were well tolerated by mice during 5- and 10-day oral toxicity studies at doses of up to 400 mg/kg of body weight. Using a nonoptimized formulation, the dihydrophthalazines displayed acceptable oral bioavailabilities in mice, and efficacy studies with a septicemia model of mice infected with trimethoprim-resistant, methicillin-resistant Staphylococcus aureus gave 50% effective dose values in the range of 1.6 to 6.25 mg/kg.
Assuntos
Antibacterianos/farmacologia , Antibacterianos/farmacocinética , Antagonistas do Ácido Fólico/farmacologia , Antagonistas do Ácido Fólico/farmacocinética , Ftalazinas/farmacologia , Ftalazinas/farmacocinética , Trimetoprima/farmacologia , Animais , Antibacterianos/química , Sobrevivência Celular/efeitos dos fármacos , Enterococcus/efeitos dos fármacos , Enterococcus/enzimologia , Antagonistas do Ácido Fólico/química , Haemophilus influenzae/efeitos dos fármacos , Haemophilus influenzae/enzimologia , Células HeLa , Humanos , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Moraxella catarrhalis/efeitos dos fármacos , Moraxella catarrhalis/enzimologia , Mycobacterium avium/efeitos dos fármacos , Mycobacterium avium/enzimologia , Ftalazinas/química , Reação em Cadeia da Polimerase , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pneumoniae/enzimologia , Tetra-Hidrofolato Desidrogenase/genética , Trimetoprima/química , Trimetoprima/farmacocinéticaRESUMO
Novel virosomal formulations of a synthetic oligosaccharide were prepared and evaluated as vaccine candidates against leishmaniasis. A lipophosphoglycan-related synthetic tetrasaccharide antigen was conjugated to a phospholipid and to the influenza virus coat protein hemagglutinin. These glycan conjugates were embedded into the lipid membrane of reconstituted influenza virus virosomes. The virosomal formulations elicited both IgM and IgG anti-glycan antibodies in mice, indicating an antibody isotype class switch to IgG. The antisera cross-reacted in vitro with the corresponding natural carbohydrate antigens expressed by leishmania cells. These findings support the concept of using virosomes as universal antigen delivery platform for synthetic carbohydrate vaccines.
Assuntos
Carboidratos/imunologia , Leishmaniose/imunologia , Polissacarídeos/imunologia , Vacinas Protozoárias , Vacinas Virossomais , Desenho de Fármacos , Glicoesfingolipídeos/síntese química , Glicoesfingolipídeos/química , Glicoesfingolipídeos/imunologia , Humanos , Oligossacarídeos/síntese química , Oligossacarídeos/imunologia , Polissacarídeos/síntese química , Virossomos/imunologiaRESUMO
Effective structural mimics of a functionally important epitope from the malarial Merozoite Surface Protein-1 (MSP-1) include N-backbone cyclic peptides such as 1. They mimic the interaction of MSP-1 with human erythrocytes and can be used to induce parasite-specific monoclonal antibodies.