Potent and rapid bactericidal action of alyteserin-1c and its [E4K] analog against multidrug-resistant strains of Acinetobacter baumannii

The emergence of multidrug-resistant strains of Acinetobacter baumannii (MDRAB) constitutes a serious threat to public health and necessitates the discovery of new types of antimicrobial agents. Alyteserin-1c (GLKEIFKAGLGSLVKGIAAHVAS·NH₂) is a cationic, α-helical peptide that was first isolated from skin secretions of the midwife toad Alytes obstetricans. Synthetic alyteserin-1c displayed potent activity against clinical isolates of MDRAB (minimum inhibitory concentration, MIC = 5-10 μM; minimum bactericidal concentration, MBC = 5-10 μM) while displaying low hemolytic activity against human erythrocytes (LD₅₀ = 220 μM). Increasing the cationicity of alyteserin-1c by the substitution Glu⁴ → Lys enhanced the potency against MDRAB (MIC = 1.25-5 μM; MBC = 1.25-5 μM) as well as decreasing hemolytic activity (HC₅₀ > 400 μM). More than 99.9% of the bacteria were killed within 30 min by the [E4K] analog at a concentration of 1 × MBC. Increasing the cationicity of [E4K]alyteserin-1c further by the additional substitutions of Ala⁸,Val¹⁴ or Ala¹⁸ by l-Lys did not enhance antimicrobial potency. Derivatives of [E4K]alyteserin-1c containing a palmitate group coupled either to α-amino group at the N-terminus or to ε-amino group on the Lys¹⁸ residue of the [E4K,A18K] analog retained antimicrobial activity but showed dramatically increased hemolytic activities (>40- and >13-fold, respectively).