Porphyrin pathways as targets for combating antimicrobial resistance: virulence and therapeutic opportunities.

Porphyrins are versatile biomolecules central to the synthesis of many essential molecules across all domains of life. Their ability to absorb light, accept electrons and facilitate redox reactions underpins diverse biological roles. Importantly, porphyrin properties can be easily tailored through substitutions of side chains and chelated metals. This adaptability has enabled porphyrins to play critical roles in bacterial environmental adaptations, most notably in enhancing competitive advantage and virulence. The association between porphyrin adaptations and virulence in pathogenic bacteria presents a unique opportunity for the development of next-generation antibacterial strategies and therapeutics. By focusing on virulence and virulence-related systems, these innovative strategies aim to address antimicrobial resistance by reducing the selective pressures that drive its emergence, promote evolutionary pathways that favor non-pathogenic adaptations and help to restore the balance of commensal microbiota. This review highlights the recent advances in porphyrin and porphyrin-related antibiotic developments, with emphasis on approaches targeting virulence versus bacterial survival. We further discuss emerging virulence-targeted therapeutics, including artificial intelligence and machine learning for novel target and lead discovery.