Platensimycin-Encapsulated Poly(lactic-co-glycolic acid) and Poly(amidoamine) Dendrimers Nanoparticles with Enhanced Anti-Staphylococcal Activity in Vivo.

Serious bacterial infections by multi-drug-resistant pathogens lead to human losses and endanger public health. The discovery of antibiotics with new modes of action, in combination with nanotechnology, might offer a promising route to combat multi-drug-resistant pathogens. Platensimycin (PTM), a potent inhibitor of FabB/FabF for bacterial fatty acid biosynthesis, is a promising drug lead against many drug-resistant bacteria. However, the clinical development of PTM is hampered by its poor pharmacokinetics. Herein, we report a nanostrategy that encapsulated PTM in two types of nanoparticles (NPs) poly(lactic-co-glycolic acid) (PLGA) and poly(amidoamine) (PAMAM) dendrimer to enhance its antibacterial activity in vitro and in vivo. The PTM-encapsulated NPs were effective to inhibit Staphylococcus aureus biofilm formation, and killed more S. aureus in a macrophage cell infection model over free PTM. The pharmacokinetic studies showed that PTM-loaded PLGA and PAMAM NPs exhibited increased AUC0-t (area under the curve) (∼4- and 2-fold) over free PTM. In a mouse peritonitis model, treatment of methicillin-resistant S. aureus infected mice using both PTM-loaded NPs (10 mg/kg) by intraperitoneal injection led to their full survival, while all infected mice died when treated by free PTM (10 mg/kg). These results not only suggest that PTM-loaded NPs may hold great potential to improve the poor pharmacokinetic properties of PTM, but support the rationale to develop bacterial fatty acid synthase inhibitors as promising antibiotics against drug-resistant pathogens.