platensimycin and Disease-Models--Animal

Topics: Adamantane; Aminobenzoates; Anilides; Animals; Biofilms; Delayed-Action Preparations; Disease Models, Animal; Drug Liberation; Humans; Hydrogels; Male; Methicillin-Resistant Staphylococcus aureus; Mice; Microbial Sensitivity Tests; Nanoparticle Drug Delivery System; Polyamines; Staphylococcal Skin Infections; Wound Healing; Wound Infection

Staphylococcus aureus is one of the most common pathogens causing hospital-acquired and community-acquired infections. Methicillin-resistant S. aureus (MRSA)-formed biofilms in wounds are difficult to treat with conventional antibiotics. By targeting FabB/FabF of bacterial fatty acid synthases, platensimycin (PTM) was discovered to act as a promising natural antibiotic against MRSA infections. In this study, PTM and its previously synthesized sulfur-Michael derivative PTM-2t could reduce over 95% biofilm formation by S. aureus ATCC 29213 when used at 2 μg/mL in vitro. Topical application of ointments containing PTM or PTM-2t (2 × 4 mg/day/mouse) was successfully used to treat MRSA infections in a BABL/c mouse burn wound model. As a potential prodrug lead, PTM-2t showed improved in vivo efficacy in a mouse peritonitis model compared with PTM. Our study suggests that PTM and its analogue may be used topically or locally to treat bacterial infections. In addition, the use of prodrug strategies might be instrumental to improve the poor pharmacokinetic properties of PTM.

Topics: Adamantane; Aminobenzoates; Anilides; Animals; Anti-Bacterial Agents; Biofilms; Burns; Disease Models, Animal; Drug Resistance, Bacterial; Drug Stability; Fatty Acid Synthase, Type II; Fatty Acid Synthesis Inhibitors; Female; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Microsomes; Peritonitis; Prodrugs; Staphylococcal Skin Infections; Sulfides; Treatment Outcome

Platensimycin (PTM), originally isolated from soil bacteria Streptomyces platensis, is a potent FabF inhibitor against many Gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci. However, the further clinical development of PTM is hampered by its poor pharmacokinetic properties. In this study, 20 PTM derivatives were prepared by Suzuki-Miyaura cross-coupling reactions catalyzed by Pd (0)/C. Compared to PTM, 6-pyrenyl PTM (6t) showed improved antibacterial activity against MRSA in a mouse peritonitis model. Our results support the strategy to target the essential fatty acid synthases in major pathogens, in order to discover and develop new generations of antibiotics.

Topics: Adamantane; Aminobenzoates; Anilides; Animals; Anti-Bacterial Agents; Disease Models, Animal; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Molecular Docking Simulation; Peritonitis; Staphylococcal Infections

Platensimycin (PTM) is a recently discovered broad-spectrum antibiotic produced by Streptomyces platensis. It acts by selectively inhibiting the elongation-condensing enzyme FabF of the fatty acid biosynthesis pathway in bacteria. We report here that PTM is also a potent and highly selective inhibitor of mammalian fatty acid synthase. In contrast to two agents, C75 and cerulenin, that are widely used as inhibitors of mammalian fatty acid synthase, platensimycin specifically inhibits fatty acid synthesis but not sterol synthesis in rat primary hepatocytes. PTM preferentially concentrates in liver when administered orally to mice and potently inhibits hepatic de novo lipogenesis, reduces fatty acid oxidation, and increases glucose oxidation. Chronic administration of platensimycin led to a net reduction in liver triglyceride levels and improved insulin sensitivity in db/+ mice fed a high-fructose diet. PTM also reduced ambient glucose levels in db/db mice. These results provide pharmacological proof of concept of inhibiting fatty acid synthase for the treatment of diabetes and related metabolic disorders in animal models.

Topics: Adamantane; Aminobenzoates; Anilides; Animals; Anti-Infective Agents; Diabetes Mellitus; Disease Models, Animal; Fatty Acid Synthases; Fatty Acids; Fatty Liver; Glucose; Humans; Hypoglycemic Agents; Liver; Mice; Mice, Mutant Strains; Oxidation-Reduction; Sterols