Activities of the frog skin peptide, ascaphin-8 and its lysine-substituted analogs against clinical isolates of extended-spectrum β-lactamase (ESBL) producing bacteria

Extended-spectrum β-lactamase (ESBL)-producing Gram-negative bacteria are becoming increasingly prevalent and their antibiotic resistance necessitates novel therapeutic intervention. Ascaphin-8 is a cationic α-helical peptide that shows broad-spectrum antibacterial activity but is also toxic to human erythrocytes (LC50 = 55 μM). This study assesses the activity of ascaphin-8, and a series of l-lysine-substituted analogs, against a range of clinical isolates of ESBL-producing bacteria. All ESBL-producing Escherichia coli (MIC = 1.5–6 μM) and Klebsiella pneumoniae (MIC = 12.5–25 μM) strains tested were susceptible to ascaphin-8, as well as a group of miscellaneous ESBL-producing strains (Citrobacter, Salmonella, Serratia, Shigella spp.) (MIC ≤ 25 μM). The Lys4- and Lys8-substituted analogs were generally the most potent against bacteria but showed the highest hemolytic activity. However, the Lys10, Lys14, and Lys18 analogs also displayed potent antibacterial activity while showing very low hemolytic activity (LC50 > 500 μM). An unexpected finding was the susceptibility of ESBL-producing Proteus mirabilis strains to ascaphin-8 (MIC = 12.5–25 μM) and its Lys4-substituted analog (MIC = 6 μM), although non-ESBL isolates of this organism were resistant to these peptides (MIC > 100 μM).