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Infections that are able to penetrate soft tissues, such as those in combat wounds, burns, and implanted medical hardware, are particularly challenging to treat. The tissue microenvironment promotes biofilm formation and, following therapy, development of multidrug resistance (MDR). We aim to develop a multifunctional precision nanomedicine for the treatment of MDR biofilm infections in these applications. Our approach features polyanionic surfactants (PS) that self-assemble with cationic antimicrobial peptides and amine-functional (e.g. aminoglycoside) antibiotics to form nanocomplexes whose properties in solution can be tailored to be favorable for delivery. In addition to encapsulating and controlling the release kinetics of cationic drugs, the PS are designed to disrupt biofilms through surfactant interfacial interactions with the biofilm’s extracellular polymeric substances (EPS). We have used these PS to encapsulate novel fusaricidin cyclic lipopeptides (from collaborator Dr. Richard Houghten of Torrey Pines Institute for Molecular Studies) and incorporated them into hydrogels with biocompatible biopolymers. These nanostructured gels exhibit effective topical antimicrobial activity in a porcine partial thickness infected wound model. We are developing this approach further to provide compatibility with antimicrobials of varying solubility and to prevent and treat hardware infections.

“GRAPLON” polyelectroloyte surfactants are used to self-assemble and encapsulate antimicrobial peptides. We have done this for novel fusaracidin cyclic lipopeptide 2579-7 and shown that its activity against MRSA infection in a porcine wound model is improved by an order of magnitude.