Biofilm-associated genes in Staphylococcus aureus: role in chronic infections and therapeutic challenges

One of the major contributors to persistent healthcare and community-associated infections is S. aureus, which has a remarkable ability to form biofilms that protect it against the host immune system and antimicrobial therapy. In recent years, it has become clear that biofilm development is a highly orchestrated and dynamic process, controlled by complex genetic networks, transcriptional regulators, two-component systems (TCSs), and environmental signals. The present review covers the molecular mechanisms involved in the initiation, maturation, maintenance, and dispersal of biofilms in general, and in particular, the coordinated functions of adhesins, the icaADBC operon, components of the extracellular matrix (ECM), global regulators (agr, sarA, and sigB), and two-component regulatory systems, as well as emerging insights from transcriptomic studies on biofilm adaptation. We then review the roles of these regulatory pathways in metabolic heterogeneity, antibiotic tolerance, immune evasion, and persistence in clinically relevant biofilm-associated infections, including infective endocarditis, osteomyelitis, prosthetic joint infection, catheter-associated infection, and diabetic foot infection. The review further outlines the latest developments in antibiofilm therapeutics, including matrix-degrading enzymes, quorum-sensing inhibitors, antimicrobial peptides, bacteriophage-based therapeutics, lysins, nitric oxide donors, nanoparticle-assisted therapeutics, and CRISPR-Cas-based antimicrobials. Incorporating molecular regulation into infection-specific pathogenesis and emerging therapeutic strategies, this review offers a new perspective on the biology of S. aureus biofilms and highlights opportunities to develop mechanism-based interventions to combat chronic biofilm-associated infections.