Small proteins and peptides conferring protection against antimicrobial compounds

The secretion of antimicrobials is widespread among microorganisms, many of which have developed protection mechanisms. While well-characterized protection mechanisms involve relatively large proteins - such as exporters or compound- or target-modifying enzymes - we discuss how small proteins and peptides can also confer protection. Recent technological advances have revealed the functional capacity and importance of the small proteome, as well as its potential for de novo evolution. We consolidate examples of diverse small proteins that play a protective role against antimicrobial agents, highlighting characteristics and exploring their mechanisms of protection where data are available. We advocate for further examination of their mechanisms of protection as they may constitute an intriguing, mechanistically, and evolutionary distinct part of the antimicrobial resistome.