Targeting S. epidermidis Biofilms by the Tetracycline-Loaded Nanogel Surface Functionalized with Savinase, DNase, and Cellulase

Persistent bacterial infections are causing millions of premature deaths worldwide due to antimicrobial resistance and biofilm formation capabilities. Among these bacteria is Staphylococcus epidermidis, which is an opportunistic pathogen commonly found on the skin and mucous membranes that can cause virulent infections when it invades the body through biomedical devices and chronic wound-related biofilms that resist antibiotic treatments. In this study, we explore three types of active nanoformulations that were developed based on surface-functionalized antibiotic-encapsulated nanogel particles (NPs) with enzymes that can potentially degrade the extracellular polymeric substance (EPS) matrix components of the S. epidermidis biofilm. This approach allows the enzyme-coated NPs loaded with an antibiotic payload to penetrate the bacterial biofilm where they can reach the residing bacterial cells and deliver antibiotic directly onto their cell walls, thus killing them. Here, polysaccharide, protein, and eDNA hydrolytic enzymes were used to functionalize tetracycline (Tc)-loaded poly(acrylic acid) copolymer nanogel particles, and their biofilm clearing ability and bactericidal effect were investigated and compared. Generally, all three enzyme-coated Tc-loaded nanogel particle formulations were found to be more effective against S. epidermidis biofilms than the equivalent concentration of free Tc. Interestingly, the polysaccharide- and protein hydrolytic enzyme-functionalized nanoformulated antibiotics performed similarly by targeting the structural basic units of the EPS matrix. These smart antibiotic nanocarriers are promising nanoformulations for overcoming biofilm-based antibiotic resistance as well as other bacterial biofilm-based resistant mechanisms and may find potential applications in chronic wound treatments.