Cationic antimicrobial peptides are ancient and ubiquitous immune effectors
that multicellular organisms use to kill and police microbes whereas
antibiotics are mostly employed by microorganisms. As antimicrobial peptides
(AMPs) mostly target the cell wall, a microbial ‘Achilles heel’, it has been
proposed that bacterial resistance evolution is very unlikely and hence AMPs
are ancient ‘weapons’ of multicellular organisms. Here we provide a new
hypothesis to explain the widespread distribution of AMPs amongst
multicellular organism. Studying five antimicrobial peptides from vertebrates
and insects, we show, using a classic Luria-Delbru¨ ck fluctuation assay, that
cationic antimicrobial peptides (AMPs) do not increase bacterial mutation
rates. Moreover, using rtPCR and disc diffusion assays we find that AMPs do
not elicit SOS or rpoS bacterial stress pathways. This is in contrast to the
main classes of antibiotics that elevate mutagenesis via eliciting the SOS and
rpoS pathways. The notion of the ‘Achilles heel’ has been challenged by
experimental selection for AMP-resistance, but our findings offer a new
perspective on the evolutionary success of AMPs. Employing AMPs seems
advantageous for multicellular organisms, as it does not fuel the adaptation
of bacteria to their immune defenses. This has important consequences for our
understanding of host-microbe interactions, the evolution of innate immune
defenses, and also sheds new light on antimicrobial resistance evolution and
the use of AMPs as drugs
