A Trade‐Off Between Antimicrobial Peptide Resistance and Sensitivity to Host Immune Effectors in <i>Staphylococcus aureus</i> In Vivo

Antimicrobial peptides (AMPs) are essential immune effectors of multicellular organisms. Bacteria can evolve resistance to AMPs. Surprisingly, when used to challenge the yellow mealworm beetle, <i>Tenebrio molitor</i>, <i>Staphylococcus aureus</i> resistant to an abundant AMP (tenecin 1) of the very same host species did not increase host mortality or bacterial load compared to infections with wild-type <i>S. aureus</i>. A possible explanation is that antimicrobial resistance is costly due to the collaterally increased sensitivity of AMP-resistant strains to other immune effectors. Here, we study the sensitivity of a group of AMP-resistant <i>S. aureus</i> strains (resistant to tenecin 1 or a combination of tenecin 1 + 2) to other immune effectors such as phenoloxidase and other AMPs in vivo. Using RNAi-based knockdown, we investigate <i>S. aureus</i> survival in insect hosts lacking selected immune effectors. We find that all except one AMP-resistant strain displayed collateral sensitivity toward phenoloxidase. Some AMP-resistant strains show sensitivity to components of the yellow mealworm beetle AMP defense cocktail. Our findings are consistent with the idea that resistance to AMPs does not translate into changes in virulence because it is balanced by the collaterally increased sensitivity to other host immune effectors. AMP resistance fails to provide a net survival advantage to <i>S. aureus</i> in a host environment that is dominated by AMPs.