RESUMO
Staphylococcus aureus is a serious threat to public health due to the rise of antibiotic resistance in this organism, which can prolong or exacerbate skin and soft tissue infections (SSTIs). Methicillin-resistant S. aureus is a Gram-positive bacterium and a leading cause of SSTIs. As such, many efforts are under way to develop therapies that target essential biological processes in S. aureus. Antimicrobial photodynamic therapy is an effective alternative to antibiotics; therefore we developed an approach to simultaneously expose S. aureus to intracellular and extracellular photosensitizers. A near infrared photosensitizer was conjugated to human monoclonal antibodies (MAbs) that target the S. aureus iron-regulated surface determinant (Isd) heme acquisition proteins. In addition, the compound VU0038882 was developed to increase photoactivatable porphyrins within the cell. Combinatorial photodynamic treatment of drug-resistant S. aureus exposed to VU0038882 and conjugated anti-Isd MAbs proved to be an effective antibacterial strategy in vitro and in a murine model of SSTIs.
Assuntos
Staphylococcus aureus Resistente à Meticilina , Infecções dos Tecidos Moles , Infecções Estafilocócicas , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Humanos , Camundongos , Fármacos Fotossensibilizantes/farmacologia , Infecções dos Tecidos Moles/tratamento farmacológico , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureusRESUMO
A novel series of 5-aryl thiazolidine-2,4-diones based dual PPARalpha/gamma agonists was identified. A number of highly potent and orally bioavailable analogues were synthesized. Efficacy study results of some of these analogues in the db/db mice model of type 2 diabetes showed them superior to rosiglitazone in correcting hyperglycemia and hypertriglyceridemia.
Assuntos
Hipoglicemiantes/síntese química , Receptores Citoplasmáticos e Nucleares/agonistas , Tiazolidinedionas/síntese química , Fatores de Transcrição/agonistas , Administração Oral , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Modelos Animais de Doenças , Hiperglicemia/tratamento farmacológico , Hipertrigliceridemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , Camundongos , Receptores Citoplasmáticos e Nucleares/metabolismo , Rosiglitazona , Relação Estrutura-Atividade , Tiazolidinedionas/farmacologia , Fatores de Transcrição/metabolismoRESUMO
A series of 5-aryl thiazolidine-2,4-diones containing 4-phenoxyphenyl side chains was designed, synthesized, and evaluated for PPAR agonist activities. One such compound 28 exhibited comparable levels of glucose correction to rosiglitazone in the db/db mouse type 2 diabetes animal model.