Proteomic Analysis of MRSA During Stress and Skin Infection: Insights and Therapeutic Targets

Methicillin-resistant Staphylococcus aureus (MRSA) is a critical public health threat, leading to recurrent skin and soft tissue infections (SSTIs). These infections often require repeated antibiotic treatments, increasing the risk of resistance. This thesis explores MRSA's adaptive stress response to environmental cues mimicking wound site conditions, such as decreased pH, temperature, and increased salinity. It also bridges the gap between experimental conditions and real-world infections by comparing the proteome of S. aureus in both in vivo (mouse model) and in vitro (3D skin model) conditions. The first study, "Comparative Proteomic Profiling of MRSA Under Varied Experimental Conditions," identified differentially expressed proteins (DEPs) under stress. Decreased pH and temperature impaired growth via disrupted purine metabolism and downregulation of inosine 5'-monophosphate dehydrogenase (IMPDH), highlighting IMPDH as a potential antimicrobial target. Sulfur metabolism was affected, with reduced cysteine synthase (CysK) compensated by increased catalase (KatA). Arginine biosynthesis proteins were highly expressed, with strain-specific adaptation strategies highlighted. The second study, "Exploring S. aureus Proteome During Skin Infection: Comparative Analysis of In Vivo and In Vitro Models," validated arginine's role in MRSA virulence. Proteins involved in betaine biosynthesis, critical for osmotic stress, were identified. Proteins associated with adaptive processes were also detected, with FumC and SapS highlighted as potential targets. The final chapter focused on antimicrobial screening, identifying paramagnetoquinones and enduracyclinones as effective agents. Additionally, two promising compounds from extracts, elaiophylin and nigericin, showed notable activity against MRSA. This research deepens our understanding of MRSA adaptation, highlights new therapeutic targets, and proposes effective antimicrobial agents to combat recurrent infections and resistance.