The emergence of multidrug-resistant
bacteria has major issues
for treating bacterial pneumonia. Currently, anoplin (GLLKRIKTLL-NH2) is a natural antimicrobial candidate derived from wasp venom.
In this study, a series of new antimicrobial peptide (AMP) anoplin
analogues were designed and synthesized. The relationship between
their biological activities and their positive charge, hydrophobicity,
amphipathicity, and secondary structure are described. The characteristic
shared by these peptides is that positively charged amino acids and
hydrophobic amino acids are severally arranged on the hydrophilic
and hydrophobic surface of the α-helix to form a completely
amphiphilic structure. To achieve ideal AMPs, below the range of the
threshold of the cytotoxicity and hemolytic activity, their charges
and hydrophobicity were increased as much. Among the new analogues,
A-21 (KWWKKWKKWW-NH2) exhibited the greatest antimicrobial
activity (geometric mean of minimum inhibitory concentrations = 4.76
μM) against all the tested bacterial strains, high bacterial
cell selectivity in vitro, high effectiveness against
bacterial pneumonia in mice infected with Klebsiella
pneumoniae, and low toxicity in mice (LD50 = 82.01 mg/kg). A-21 exhibited a potent bacterial membrane-damaging
mechanism and lipopolysaccharide-binding ability. These data provide
evidence that A-21 is a promising antimicrobial candidate for the
treatment of bacterial pneumonia.