Disclosed herein are novel antimicrobial peptides with useful, improved, or superior properties such as antimicrobial activity, specificity, resistance to degradation desirable levels of hemolytic activity, and therapeutic index against a broad range of microorganisms including gram-negative and gram-positive bacteria and other organisms having a cellular or structural component of a lipid bilayer membrane. Also provided are methods of making and using such peptides to control microbial growth and in pharmaceutical compositions for treatment or prevention of infections caused by such microorganisms. Certain peptides result from structure-based rational design relating to antimicrobial peptide V681, with single D-/L-amino acid substitutions or charged residue substitutions in or near the center of the peptide on the nonpolar or polar face. Some peptides contain one or more (or all) amino acids in the D configuration. Compositions disclosed herein have useful clinical potential as antibiotics including broad spectrum antibiotics.
