Collateral sensitivity: negative pleiotropy in Staphylococcus aureus resistance to host immune effectors

Abstract

Antimicrobial peptides (AMP) are essential immune effectors of multicellular organisms. Bacteria can evolve resistance to AMPs. Surprisingly, when used to challenge the insect Tenebrio molitor, Staphylococcus aureus 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 S. aureus. A possible explanation is that antimicrobial resistance is costly due to collaterally increased sensitivity of AMP-resistant strains to other immune effectors. We studied the sensitivity of a group of AMP-resistant S. aureus 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 investigated S. aureus survival in insect hosts lacking selected immune effectors. We found that all except one AMP-resistant strain displayed collateral sensitivity toward phenoloxidase. Some AMP-resistant strains showed sensitivity to components of the beetle AMP defence cocktail. Our findings are consistent with the idea that resistance to AMPs does not translate into changes in virulence because it is balanced by collaterally increased sensitivity to other host immune effectors. AMP resistance fails to provide a net survival advantage to S. aureus in a host environment that is dominated by AMPs.