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Antimicrobial Properties of Brevinin‐2‐Related Peptide and its Analogs: Efficacy Against Multidrug‐Resistant Acinetobacter baumannii
Author(s) -
Conlon J. Michael,
Ahmed Eman,
Condamine Eric
Publication year - 2009
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2009.00882.x
Subject(s) - acinetobacter baumannii , antimicrobial , potency , microbiology and biotechnology , minimum inhibitory concentration , staphylococcus aureus , multiple drug resistance , biology , antibiotics , bacteria , chemistry , pseudomonas aeruginosa , biochemistry , in vitro , genetics
Brevinin‐2 related peptide (B2RP; GIWDTIKSMG 10 KVFAGKILQN 20 L.NH 2 ), first isolated from skin secretions of the mink frog Lithobates septentrionalis , shows broad‐spectrum antimicrobial activity but its therapeutic potential is limited by moderate hemolytic activity. The peptide adopts an α‐helical conformation in a membrane‐mimetic solvent but amphipathicity is low. Increasing amphipathicity together with hydrophobicity by the substitutions Lys 16 →Leu and Lys 16 →Ala increased hemolytic activity approximately fivefold without increasing antimicrobial potency. The substitution Leu 18 →Lys increased both cationicity and amphipathicity but produced decreases in both antimicrobial potency and hemolytic activity. In contrast, increasing cationicity of B2RP without changing amphipathicity by the substitution Asp 4 →Lys resulted in a fourfold increase in potency against Escherichia coli [minimal inhibitory concentration (MIC) = 6 μ m ) and twofold increases in potency against Staphylococcus aureus (MIC = 12.5 μ m ) and Candida albicans (MIC = 6 μ m ) without changing significantly hemolytic activity against human erythrocytes (LC 50 = 95 μ m ). The emergence of antibiotic‐resistant strains of the Gram‐negative bacterium Acinetobacter baumannii constitutes a serious risk to public health. B2RP (MIC = 3–6 μ m ) and [Lys 4 ]B2RP (MIC = 1.5–3 μ m ) potently inhibited the growth of nosocomial isolates of multidrug‐resistant Acinetobacter baumannii . Although the analogs [Lys 4 , Lys 18 ]B2RP and [Lys 4 , Ala 16 , Lys 18 ]B2RP showed reduced potency against Staphylococcus aureus , they retained activity against Acinetobacter baumannii (MIC = 3–6 μ m ) and had very low hemolytic activity (LC 50 > 200 μ m ).