ABSTRACT
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.
Subject(s)
Methicillin-Resistant Staphylococcus aureus , Soft Tissue Infections , Staphylococcal Infections , Animals , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Humans , Mice , Photosensitizing Agents/pharmacology , Soft Tissue Infections/drug therapy , Staphylococcal Infections/drug therapy , Staphylococcus aureusABSTRACT
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.
Subject(s)
Hypoglycemic Agents/chemical synthesis , Receptors, Cytoplasmic and Nuclear/agonists , Thiazolidinediones/chemical synthesis , Transcription Factors/agonists , Administration, Oral , Animals , Diabetes Mellitus, Type 2/drug therapy , Disease Models, Animal , Hyperglycemia/drug therapy , Hypertriglyceridemia/drug therapy , Hypoglycemic Agents/pharmacology , Mice , Receptors, Cytoplasmic and Nuclear/metabolism , Rosiglitazone , Structure-Activity Relationship , Thiazolidinediones/pharmacology , Transcription Factors/metabolismABSTRACT
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.