Alternative and Synergistic Strategies Against Antibiotic-Resistant Staphylococcus aureus in Clinical and Environmental Settings.

Antimicrobial resistance (AMR) in Staphylococcus aureus (S. aureus) poses a serious global health threat, undermining treatment outcomes and necessitating the development of innovative therapeutic strategies. Methicillin-resistant Staphylococcus aureus (MRSA) is a major contributor to this burden, with increasing prevalence in hospitals, contaminated food, and environmental sources. The coronavirus disease 2019 (COVID-19) pandemic further intensified S. aureus resistance due to widespread antibiotic misuse. Biofilm formation, which facilitates the horizontal transfer of resistance genes such as mecA (methicillin resistance gene A), plays a central role in the development of resistance. To counteract antibiotic-resistant S. aureus, alternative approaches have emerged, including antimicrobial peptides (AMPs), photodynamic therapy (PDT), and drug repurposing guided by artificial intelligence (AI). Cutting-edge technologies such as clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 13a (Cas13a)-based gene editing and engineered bacteriophages offer promising avenues for targeting resistant strains. Natural compounds such as thymol and chlorogenic acid (CGA) have also shown potential in reducing resistance and inhibiting biofilm formation. Effective management of AMR requires strengthened antibiotic stewardship programs (ASPs), robust surveillance systems, and public health measures such as proper hand hygiene and environmental sanitation. Combining antibiotic adjuvants (AAs) with existing antibiotics and leveraging bioactive peptides (BAPs) can enhance antibiotic efficacy against multidrug-resistant (MDR), extensively drug-resistant (XDR), and pan-drug-resistant (PDR) S. aureus. This review investigates the prevalence and resistance mechanisms of S. aureus in clinical, food, and environmental contexts, explores promising alternative therapies, and emphasizes the urgent need for global antimicrobial stewardship (AMS) and sustainable intervention strategies.