SET-M33 loaded biosynthesized cellulose as effective protection against S. aureus biofilm formation

<i>Staphylococcus aureus</i> is the most common pathogen responsible for postoperative infections associated with cardiac implantable electronic devices (CIEDs), primarily due to its biofilm-forming capability on implant substrates<i>.</i> Protective envelopes, which sustain the local elution of antibiotics, significantly reduce the risk of CIED infection and biofilm formation. However, they are not equipped to counteract emerging bacterial resistance to antibiotics. Antimicrobial peptides (AMPs) can effectively erase contaminating bacteria, without eliciting resistance. Here, we explored the antimicrobial efficacy of biosynthesized cellulose (BC), a natural biopolymer used in protective envelopes, in combination with two synthetic AMPs: SET-M33D and Mastoparan X (MPX). The BC/AMPs combination inhibited bacterial attachment and subsequent biofilm formation significantly better than native BC or AMP coated titanium substrates, as revealed by full factorial design (FFD) experiments. The outcomes of FFD were used to develop a regression model that estimates the interaction between influential parameters and their impacts on response value. Furthermore, SEM imaging confirmed the superior antibiofilm activity of BC/SET-M33D compared to BC/MPX. We demonstrated that the protective function against <i>S. aureus</i> ATCC29213 may be linked to the downregulation of the biofilm associated gene <i>icaA</i>. The results reported demonstrate the feasibility of exploiting BC as AMP carrier for inhibiting biofilm formation in conditions relevant to deployment of CIEDs. While further in vivo evaluation is needed, this approach may offer a promising path to address antimicrobial resistance in the management of post-operative infections associated with CIED implant.