Endophytic fungi as a source of antimicrobial compounds against emerging methicillin-resistant Staphylococcus aureus

Antimicrobial resistance (AMR) represents a critical global health threat, significantly impacting treatment outcomes, increasing mortality, and imposing economic burdens. It also hinders progress towards Sustainable Development Goal (SDG) 3: Good Health and Well-being. Among the most concerning resistant pathogens is Methicillin-resistant Staphylococcus aureus (MRSA), a multidrug-resistant bacterium whose genetic adaptability and rapid evolution have rendered many conventional antibiotics ineffective. The clinical and agricultural use and misuse of antimicrobial agents is hastening the development of resistant strains, and there is an urgent need for new therapeutics to address this issue. Endophytic fungi live asymptomatically within plant tissues and have great potential as a largely unexplored source of structurally diverse secondary metabolites that can exhibit potent antibacterial properties. This review aims to highlight the classes of fungal metabolites that are active against MRSA, including alkaloids, polyketides, terpenoids, peptides, flavonoids, and quinones, while describing their mechanisms of action, which include inhibition of cell wall biosynthesis, disruption of biofilm production, and inhibition of nucleic acid or protein synthesis. The review will also highlight the ecological relevance of endophytes and structure–activity relationships (SAR) as they relate to drug development. By aligning with aspects of the “One Health” prescription for integrating the health of humans, animals, and the environment, the present review highlights the viability of endophytic fungi as compelling players in the global response to AMR—and brings the potential of the use of natural products in a more sustainable manner to promote and develop more antimicrobial strategies in all sectors.