Computer-Aided Design of Mastoparan-like Peptides Enables the Generation of Nontoxic Variants with Extended Antibacterial Properties

Diverse peptides
have been evaluated for their activity against
pathogenic microorganisms. Here, five mastoparan variants were designed
based on mastoparan-L, among which two (R1 and R4) were selected for
in-depth analysis. Mastoparan-L (parent/control), R1, and R4 inhibited
susceptible/resistant bacteria at concentrations ranging from 2 to
32 μM, whereas only R1 and R4 eradicated Pseudomonas
aeruginosa biofilms at 16 μM. Moreover, the
toxic effects of mastoparan-L toward mammalian cells were drastically
reduced in both variants. In skin infections, R1 at 64 μM was
the most effective variant, reducing P. aeruginosa bacterial counts 1000 times on day 4 post-infection. Structurally,
all of the peptides showed varying levels of helicity and structural
stability in aqueous and membrane-like conditions, which may affect
the different bioactivities observed here. By computationally modifying
the physicochemical properties of R1 and R4, we reduced the cytotoxicity
and optimized the therapeutic potential of these mastoparan-like peptides
both in vitro and in vivo.