FibriLysins disrupt Staphylococcus aureus biofilms and abscess communities.

The rise of antibiotic resistance, particularly among pathogens such as methicillin-resistant Staphylococcus aureus, necessitates innovative antibacterial strategies. Here we introduce FibriLysins, a class of engineered enzymes combining staphylokinase and endolysin, which dismantle fibrin-encapsulated multicellular staphylococcal communities, including biofilms and staphylococcal abscess communities (SACs). We characterized diverse staphylokinases, developing a library of 27 FibriLysins, with a 78% positive hit rate. The lead variant, FL-028, has significant antibacterial activity against prevalent clinical S. aureus isolates. In vitro, FL-028 reduced bacterial counts in SACs by 3.4 log and in biofilms by 2.3 log. In vivo, FL-028 exhibits superior efficacy in a mouse model of bone fracture-related infection, outperforming vancomycin by 1 log and eliminating SAC presence in tissues. FL-028 shows no adverse effects on bone healing, as confirmed by histological examination, mechanical testing and micro-computed tomography analyses. These preclinical findings highlight the potential of FibriLysins as a robust and safe therapeutic approach against difficult-to-treat staphylococcal infections.