Activities of the frog skin peptide, ascaphin-8 and its lysine-substituted analogs against clinical isolates of extended-spectrum beta-lactamase (ESBL) producing bacteria.
Extended-spectrum beta-lactamase (ESBL)-producing Gram-negative bacteria are becoming increasingly prevalent and their antibiotic resistance necessitates novel therapeutic intervention. Ascaphin-8 is a cationic alpha-helical peptide that shows broad-spectrum antibacterial activity but is also toxic to human erythrocytes (LC(50)= 55 microM). 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 microM) and Klebsiella pneumoniae (MIC=12.5-25 microM) strains tested were susceptible to ascaphin-8, as well as a group of miscellaneous ESBL-producing strains (Citrobacter, Salmonella, Serratia, Shigella spp.) (MIC< or = 25 microM). 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 microM). An unexpected finding was the susceptibility of ESBL-producing Proteus mirabilis strains to ascaphin-8 (MIC=12.5-25 microM) and its Lys4-substituted analog (MIC= 6 microM), although non-ESBL isolates of this organism were resistant to these peptides (MIC> 100 microM).
Eley
Adrian
A
Department of Medical Microbiology, Faculty of Medicine and Health Sciences, United Arab Emirates University, 17666 Al Ain, United Arab Emirates.
Ibrahim
Marwa
M
Kurdi
Sylvia El
SE
Conlon
J Michael
JM
D029845:Amphibian Proteins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001001:Anura; D004305:Dose-Response Relationship, Drug; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology / Q000302:isolation & purification; D007711:Klebsiella pneumoniae / Q000187:drug effects* / Q000201:enzymology / Q000302:isolation & purification; D008239:Lysine / Q000737:chemistry*; D008826:Microbial Sensitivity Tests; D011513:Proteus mirabilis / Q000187:drug effects* / Q000201:enzymology / Q000302:isolation & purification; D012867:Skin / Q000737:chemistry; D001618:beta-Lactamases / Q000096:biosynthesis
D029845:Amphibian Proteins; D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; C527844:ascaphin-8 peptide, Ascaphus truei; D001618:beta-Lactamases; D008239:Lysine