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 ɛ-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).

Research highlights▶ Alyteserin-1c is active against multidrug resistant strains of Acinetobacter baumannii (MDRAB). ▶ The analog [E4K]alyteserin-1c shows increased potency relative to the natural peptide and is non-toxic. ▶ [E4K]alyteserin-1c is bactericidal producing rapid cell death. ▶ Palmitoylated analogs of [E4K]alyteserin-1c are strongly hemolytic.