Background: Antimicrobial resistance (AMR) to conventional antibiotics is becoming one of the main global health threats and novel alternative strategies are urging. Antimicrobial peptides (AMPs), once forgotten, are coming back into the scene as promising tools to overcome bacterial resistance. Recent findings have attracted attention to the potentiality of AMPs to work as antibiotic adjuvants.

Methods: In this review, we have tried to collect the currently available information on the mechanism of action of AMPs in synergy with other antimicrobial agents. In particular, we have focused on the mechanisms of action that mediate the inhibition of the emergence of bacterial resistance by AMPs.

Results and Conclusion: We find in the literature many examples where AMPs can significantly reduce the antibiotic effective concentration. Mainly, the peptides work at the bacterial cell wall and thereby facilitate the drug access to its intracellular target. Complementarily, AMPs can also contribute to permeate the exopolysaccharide layer of biofilm communities, or even prevent bacterial adhesion and biofilm growth. Secondly, we find other peptides that can directly block the emergence of bacterial resistance mechanisms or interfere with the community quorum-sensing systems. Interestingly, the effective peptide concentrations for adjuvant activity and inhibition of bacterial resistance are much lower than the required for direct antimicrobial action. Finally, many AMPs expressed by innate immune cells are endowed with immunomodulatory properties and can participate in the host response against infection. Recent studies in animal models confirm that AMPs work as adjuvants at non-toxic concentrations and can be safely administrated for novel combined chemotherapies.