Hydrophobicity Determines the Bacterial Killing Rate of α‑Helical Antimicrobial Peptides and Influences the Bacterial Resistance Development

Rapid
antimicrobial action is an important advantage of antimicrobial
peptides (AMPs) over antibiotics, which is also a reason for AMPs
being less likely to induce bacterial resistance. However, the structural
parameters and underlying mechanisms affecting the bacterial killing
rate of AMPs remain unknown. In this study, we performed a structure–activity
relationship (SAR) study using As-CATH4 and 5 as templates. We revealed
that hydrophobicity, rather than other characteristics, is the critical
structural parameter determining the bacterial killing rate of α-helical
AMPs. With the hydrophobicity increase, the action rates of AMPs including
bacterial binding, lipopolysaccharides neutralization, and outer and
inner membrane permeabilization increased. Additionally, the higher
hydrophobic AMPs with enhanced bacterial killing rates possess better in vivo therapeutic potency and a lower propensity to induce
bacterial resistance. These findings revealed the importance of the
bacterial killing rate for AMPs and are of great significance to the
design and optimization of AMP-related drugs.