The emergence of multidrug-resistant strains of Acinetobacter baumannii (MDRAB) constitutes a ser... more 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).▶ 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.
Comparative Biochemistry and Physiology C-toxicology & Pharmacology, 2010
Nine peptides with differential growth inhibitory activity against Escherichia coli and Staphyloc... more Nine peptides with differential growth inhibitory activity against Escherichia coli and Staphylococcus aureus were isolated from norepinephrine-stimulated skin secretions of the tetraploid frog Xenopus borealis Parker, 1936 (Pipidae). Structural characterization of the peptides demonstrated that they were orthologous to magainin-2 (1 peptide), peptide glycine–leucine-amide, PGLa (2 peptides), caerulein-precursor fragments, CPF (4 peptides), and xenopsin-precursor fragments, XPF (2 peptides), previously isolated from Xenopus laevis and X. amieti. In addition, a second magainin-related peptide (G**KFLHSAGKFGKAFLGEVMIG) containing a two amino acid residue deletion compared with magainin-2 was identified that had only weak antimicrobial activity. The peptide with the greatest potential for development into a therapeutically valuable anti-infective agent was CPF-B1 (GLGSLLGKAFKIGLKTVGKMMGGAPREQ) with MIC = 5 μM against E. coli, MIC = 5 μM against S. aureus, and MIC = 25 μM against Candida albicans, and low hemolytic activity against human erythrocytes (LC50 > 200 μM). This peptide was also the most abundant antimicrobial peptide in the skin secretions. CPF-B1 was active against clinical isolates of the nosocomial pathogens, methicillin-resistant S. aureus (MRSA) and multidrug-resistant Acinetobacter baumannii (MDRAB) with MIC values in the range 4–8 μM.
ABSTRACT New nicotinic acid derivatives (IV) display distinctive analgesic and antiinflammatory a... more ABSTRACT New nicotinic acid derivatives (IV) display distinctive analgesic and antiinflammatory activities in comparison to mefenamic acid as reference drug.
Population declines due to chytridiomycosis among frogs belonging to the Amerana (Rana boylii) sp... more Population declines due to chytridiomycosis among frogs belonging to the Amerana (Rana boylii) species group from western North America have been particularly severe. Norepinephrine-stimulated skin secretions from the Oregon spotted frog Rana pretiosa Baird and Girard, 1853 were collected from individuals that had been previously infected with the causative agent Batrachochytrium dendrobatidis but had proved resistant to developing chytridiomycosis. These secretions contained a more diverse array of antimicrobial peptides than found in other species from the Amerana group and 14 peptides were isolated in pure form. Determination of their primary structures identified the peptides as esculentin-2PRa and -2PRb; ranatuerin-2PRa, -2PRb, -2PRc, -2PRd, and -2PRe; brevinin-1PRa, -1PRb, -1PRc, and -1PRd; and temporin-PRa, -PRb, and -PRc. The strongly cationic ranatuerin-2PRd and the esculentin-2 peptides, which have not been identified in the secretions of other Amerana species except for the closely related R. luteiventris, showed the highest growth inhibitory potency against microorganisms. The strongly hydrophobic brevinin-1PRd was the most cytotoxic to erythrocytes. Although no clear correlation exists between production of dermal antimicrobial peptides by a species and its resistance to fatal chytridiomycosis, the diversity of these peptides in R. pretiosa may be pivotal in defending the species against environmental pathogens such as B. dendrobatidis.
Mueller&a... more Mueller's clawed frog Xenopus muelleri (Peters 1844) occupies two non-contiguous ranges in east and west Africa. The phylogenetic relationship between the two populations is unclear and it has been proposed that the western population represents a separate species. Peptidomic analysis of norepinephrine-stimulated skin secretions from X. muelleri from the eastern range resulted in the identification of five antimicrobial peptides structurally related to the magainins (magainin-M1 and -M2), xenopsin-precursor fragments (XPF-M1) and caerulein-precursor fragments (CPF-M1 and -M2) previously found in skin secretions of other Xenopus species. A cyclic peptide (WCPPMIPLCSRF.NH₂) containing the RFamide motif was also isolated that shows limited structural similarity to the tigerinins, previously identified only in frogs of the Dicroglossidae family. The components identified in skin secretions from X. muelleri from the western range comprised one magainin (magainin-MW1), one XPF peptide (XPF-MW1), two peptides glycine-leucine amide (PGLa-MW1 and -MW2), and three CPF peptides (CPF-MW1, -MW2 and -MW3). Comparison of the primary structures of these peptides suggest that western population of X. muelleri is more closely related to X. borealis than to X. muelleri consistent with its proposed designation as a separate species. The CPF peptides showed potent, broad-spectrum activity against reference strains of bacteria (MIC 3-25 μM), but were hemolytic against human erythrocytes.
The emergence of multidrug-resistant strains of Acinetobacter baumannii (MDRAB) constitutes a ser... more 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·NH(2)) 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 (LD(50)=220 μM). Increasing the cationicity of alyteserin-1c by the substitution Glu(4)→Lys enhanced the potency against MDRAB (MIC=1.25-5 μM; MBC=1.25-5 μM) as well as decreasing hemolytic activity (HC(50)>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 Ala(8),Val(14) or Ala(18) 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 Lys(18) residue of the [E4K,A18K] analog retained antimicrobial activity but showed dramatically increased hemolytic activities (>40- and >13-fold, respectively).
ABSTRACT Novel 4-(4-bromophenyl)phthalazine and phthalazinone derivatives connected through 2-pro... more ABSTRACT Novel 4-(4-bromophenyl)phthalazine and phthalazinone derivatives connected through 2-propanol spacer to N-substituted piperazine residue were synthesized. All the new compounds were screened for their effect on β-adrenergic blocking activity on the norepinephrine-induced precontracted aortic ring module. Most test compounds displayed appreciable β-adrenolytic activity compared to propranolol as a reference standard. The results have shown that compounds 3a, 3d, 3e and 7c displayed appreciable inhibition of norepinephrine-induced aortic ring contraction.
Temporin-1DRa (HFLGTLVNLAKKIL.NH2), first isolated from the skin of the California red-legged fro... more Temporin-1DRa (HFLGTLVNLAKKIL.NH2), first isolated from the skin of the California red-legged frog Rana draytonii, shows broad-spectrum antimicrobial activity but its therapeutic potential is limited by its toxicity against mammalian cells. The cytolytic properties of cationic α-helical peptides are determined by a complex interaction between cationicity, hydrophobicity, conformation, and amphipathicity. This study has investigated the cytolytic properties of conformationally constrained analogs of temporin-1DRa containing α-aminoisobutyric acid (Aib) substitutions. Cytolytic activity was determined against the bacteria Escherichia coli and Staphylococcus aureus, the opportunistic yeast pathogen, Candida albicans, human erythrocytes, HepG2 hepatoma-derived cells, and L929 fibroblasts. Aib substitutions at Gly4, Asn8, and Ala10 increased both % helicity, determined in methanol solution, and hydrophobicity resulting in increases in both antimicrobial potencies and toxicities against the mammalian cells. Substitution at Leu6 resulted in an appreciable decrease in cytolytic activity against all cells whereas the substitutions at His1, Phe2, Leu3, Thr5, and Val7 had only minor effects on activity. Substitutions at Leu9, Ile13, Leu14 produced analogs with decreased helicity and hydrophobicity that retained activity against microorganisms but showed appreciably lower cytolytic activities against mammalian cells. In particular, the fourfold increase in therapeutic index [ratio of LC50 against erythrocytes to minimum inhibitory concentration (MIC) against microorganisms] of [Aib13]temporin-1DRa identifies it as a compound with potential for development as a therapeutically valuable anti-infective agent.
Comparative biochemistry and physiology. Toxicology & pharmacology : CBP, 2010
Nine peptides with differential growth inhibitory activity against Escherichia coli and Staphyloc... more Nine peptides with differential growth inhibitory activity against Escherichia coli and Staphylococcus aureus were isolated from norepinephrine-stimulated skin secretions of the tetraploid frog Xenopus borealis Parker, 1936 (Pipidae). Structural characterization of the peptides demonstrated that they were orthologous to magainin-2 (1 peptide), peptide glycine–leucine-amide, PGLa (2 peptides), caerulein-precursor fragments, CPF (4 peptides), and xenopsin-precursor fragments, XPF (2 peptides), previously isolated from Xenopus laevis and X. amieti. In addition, a second magainin-related peptide (G**KFLHSAGKFGKAFLGEVMIG) containing a two amino acid residue deletion compared with magainin-2 was identified that had only weak antimicrobial activity. The peptide with the greatest potential for development into a therapeutically valuable anti-infective agent was CPF-B1 (GLGSLLGKAFKIGLKTVGKMMGGAPREQ) with MIC = 5 μM against E. coli, MIC = 5 μM against S. aureus, and MIC = 25 μM against Candida albicans, and low hemolytic activity against human erythrocytes (LC50 > 200 μM). This peptide was also the most abundant antimicrobial peptide in the skin secretions. CPF-B1 was active against clinical isolates of the nosocomial pathogens, methicillin-resistant S. aureus (MRSA) and multidrug-resistant Acinetobacter baumannii (MDRAB) with MIC values in the range 4–8 μM.
The emergence of multidrug-resistant strains of Acinetobacter baumannii (MDRAB) constitutes a ser... more 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).▶ 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.
Comparative Biochemistry and Physiology C-toxicology & Pharmacology, 2010
Nine peptides with differential growth inhibitory activity against Escherichia coli and Staphyloc... more Nine peptides with differential growth inhibitory activity against Escherichia coli and Staphylococcus aureus were isolated from norepinephrine-stimulated skin secretions of the tetraploid frog Xenopus borealis Parker, 1936 (Pipidae). Structural characterization of the peptides demonstrated that they were orthologous to magainin-2 (1 peptide), peptide glycine–leucine-amide, PGLa (2 peptides), caerulein-precursor fragments, CPF (4 peptides), and xenopsin-precursor fragments, XPF (2 peptides), previously isolated from Xenopus laevis and X. amieti. In addition, a second magainin-related peptide (G**KFLHSAGKFGKAFLGEVMIG) containing a two amino acid residue deletion compared with magainin-2 was identified that had only weak antimicrobial activity. The peptide with the greatest potential for development into a therapeutically valuable anti-infective agent was CPF-B1 (GLGSLLGKAFKIGLKTVGKMMGGAPREQ) with MIC = 5 μM against E. coli, MIC = 5 μM against S. aureus, and MIC = 25 μM against Candida albicans, and low hemolytic activity against human erythrocytes (LC50 > 200 μM). This peptide was also the most abundant antimicrobial peptide in the skin secretions. CPF-B1 was active against clinical isolates of the nosocomial pathogens, methicillin-resistant S. aureus (MRSA) and multidrug-resistant Acinetobacter baumannii (MDRAB) with MIC values in the range 4–8 μM.
ABSTRACT New nicotinic acid derivatives (IV) display distinctive analgesic and antiinflammatory a... more ABSTRACT New nicotinic acid derivatives (IV) display distinctive analgesic and antiinflammatory activities in comparison to mefenamic acid as reference drug.
The emergence of multidrug-resistant strains of Acinetobacter baumannii (MDRAB) constitutes a ser... more 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).▶ 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.
Comparative Biochemistry and Physiology C-toxicology & Pharmacology, 2010
Nine peptides with differential growth inhibitory activity against Escherichia coli and Staphyloc... more Nine peptides with differential growth inhibitory activity against Escherichia coli and Staphylococcus aureus were isolated from norepinephrine-stimulated skin secretions of the tetraploid frog Xenopus borealis Parker, 1936 (Pipidae). Structural characterization of the peptides demonstrated that they were orthologous to magainin-2 (1 peptide), peptide glycine–leucine-amide, PGLa (2 peptides), caerulein-precursor fragments, CPF (4 peptides), and xenopsin-precursor fragments, XPF (2 peptides), previously isolated from Xenopus laevis and X. amieti. In addition, a second magainin-related peptide (G**KFLHSAGKFGKAFLGEVMIG) containing a two amino acid residue deletion compared with magainin-2 was identified that had only weak antimicrobial activity. The peptide with the greatest potential for development into a therapeutically valuable anti-infective agent was CPF-B1 (GLGSLLGKAFKIGLKTVGKMMGGAPREQ) with MIC = 5 μM against E. coli, MIC = 5 μM against S. aureus, and MIC = 25 μM against Candida albicans, and low hemolytic activity against human erythrocytes (LC50 > 200 μM). This peptide was also the most abundant antimicrobial peptide in the skin secretions. CPF-B1 was active against clinical isolates of the nosocomial pathogens, methicillin-resistant S. aureus (MRSA) and multidrug-resistant Acinetobacter baumannii (MDRAB) with MIC values in the range 4–8 μM.
ABSTRACT New nicotinic acid derivatives (IV) display distinctive analgesic and antiinflammatory a... more ABSTRACT New nicotinic acid derivatives (IV) display distinctive analgesic and antiinflammatory activities in comparison to mefenamic acid as reference drug.
Population declines due to chytridiomycosis among frogs belonging to the Amerana (Rana boylii) sp... more Population declines due to chytridiomycosis among frogs belonging to the Amerana (Rana boylii) species group from western North America have been particularly severe. Norepinephrine-stimulated skin secretions from the Oregon spotted frog Rana pretiosa Baird and Girard, 1853 were collected from individuals that had been previously infected with the causative agent Batrachochytrium dendrobatidis but had proved resistant to developing chytridiomycosis. These secretions contained a more diverse array of antimicrobial peptides than found in other species from the Amerana group and 14 peptides were isolated in pure form. Determination of their primary structures identified the peptides as esculentin-2PRa and -2PRb; ranatuerin-2PRa, -2PRb, -2PRc, -2PRd, and -2PRe; brevinin-1PRa, -1PRb, -1PRc, and -1PRd; and temporin-PRa, -PRb, and -PRc. The strongly cationic ranatuerin-2PRd and the esculentin-2 peptides, which have not been identified in the secretions of other Amerana species except for the closely related R. luteiventris, showed the highest growth inhibitory potency against microorganisms. The strongly hydrophobic brevinin-1PRd was the most cytotoxic to erythrocytes. Although no clear correlation exists between production of dermal antimicrobial peptides by a species and its resistance to fatal chytridiomycosis, the diversity of these peptides in R. pretiosa may be pivotal in defending the species against environmental pathogens such as B. dendrobatidis.
Mueller&a... more Mueller's clawed frog Xenopus muelleri (Peters 1844) occupies two non-contiguous ranges in east and west Africa. The phylogenetic relationship between the two populations is unclear and it has been proposed that the western population represents a separate species. Peptidomic analysis of norepinephrine-stimulated skin secretions from X. muelleri from the eastern range resulted in the identification of five antimicrobial peptides structurally related to the magainins (magainin-M1 and -M2), xenopsin-precursor fragments (XPF-M1) and caerulein-precursor fragments (CPF-M1 and -M2) previously found in skin secretions of other Xenopus species. A cyclic peptide (WCPPMIPLCSRF.NH₂) containing the RFamide motif was also isolated that shows limited structural similarity to the tigerinins, previously identified only in frogs of the Dicroglossidae family. The components identified in skin secretions from X. muelleri from the western range comprised one magainin (magainin-MW1), one XPF peptide (XPF-MW1), two peptides glycine-leucine amide (PGLa-MW1 and -MW2), and three CPF peptides (CPF-MW1, -MW2 and -MW3). Comparison of the primary structures of these peptides suggest that western population of X. muelleri is more closely related to X. borealis than to X. muelleri consistent with its proposed designation as a separate species. The CPF peptides showed potent, broad-spectrum activity against reference strains of bacteria (MIC 3-25 μM), but were hemolytic against human erythrocytes.
The emergence of multidrug-resistant strains of Acinetobacter baumannii (MDRAB) constitutes a ser... more 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·NH(2)) 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 (LD(50)=220 μM). Increasing the cationicity of alyteserin-1c by the substitution Glu(4)→Lys enhanced the potency against MDRAB (MIC=1.25-5 μM; MBC=1.25-5 μM) as well as decreasing hemolytic activity (HC(50)>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 Ala(8),Val(14) or Ala(18) 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 Lys(18) residue of the [E4K,A18K] analog retained antimicrobial activity but showed dramatically increased hemolytic activities (>40- and >13-fold, respectively).
ABSTRACT Novel 4-(4-bromophenyl)phthalazine and phthalazinone derivatives connected through 2-pro... more ABSTRACT Novel 4-(4-bromophenyl)phthalazine and phthalazinone derivatives connected through 2-propanol spacer to N-substituted piperazine residue were synthesized. All the new compounds were screened for their effect on β-adrenergic blocking activity on the norepinephrine-induced precontracted aortic ring module. Most test compounds displayed appreciable β-adrenolytic activity compared to propranolol as a reference standard. The results have shown that compounds 3a, 3d, 3e and 7c displayed appreciable inhibition of norepinephrine-induced aortic ring contraction.
Temporin-1DRa (HFLGTLVNLAKKIL.NH2), first isolated from the skin of the California red-legged fro... more Temporin-1DRa (HFLGTLVNLAKKIL.NH2), first isolated from the skin of the California red-legged frog Rana draytonii, shows broad-spectrum antimicrobial activity but its therapeutic potential is limited by its toxicity against mammalian cells. The cytolytic properties of cationic α-helical peptides are determined by a complex interaction between cationicity, hydrophobicity, conformation, and amphipathicity. This study has investigated the cytolytic properties of conformationally constrained analogs of temporin-1DRa containing α-aminoisobutyric acid (Aib) substitutions. Cytolytic activity was determined against the bacteria Escherichia coli and Staphylococcus aureus, the opportunistic yeast pathogen, Candida albicans, human erythrocytes, HepG2 hepatoma-derived cells, and L929 fibroblasts. Aib substitutions at Gly4, Asn8, and Ala10 increased both % helicity, determined in methanol solution, and hydrophobicity resulting in increases in both antimicrobial potencies and toxicities against the mammalian cells. Substitution at Leu6 resulted in an appreciable decrease in cytolytic activity against all cells whereas the substitutions at His1, Phe2, Leu3, Thr5, and Val7 had only minor effects on activity. Substitutions at Leu9, Ile13, Leu14 produced analogs with decreased helicity and hydrophobicity that retained activity against microorganisms but showed appreciably lower cytolytic activities against mammalian cells. In particular, the fourfold increase in therapeutic index [ratio of LC50 against erythrocytes to minimum inhibitory concentration (MIC) against microorganisms] of [Aib13]temporin-1DRa identifies it as a compound with potential for development as a therapeutically valuable anti-infective agent.
Comparative biochemistry and physiology. Toxicology & pharmacology : CBP, 2010
Nine peptides with differential growth inhibitory activity against Escherichia coli and Staphyloc... more Nine peptides with differential growth inhibitory activity against Escherichia coli and Staphylococcus aureus were isolated from norepinephrine-stimulated skin secretions of the tetraploid frog Xenopus borealis Parker, 1936 (Pipidae). Structural characterization of the peptides demonstrated that they were orthologous to magainin-2 (1 peptide), peptide glycine–leucine-amide, PGLa (2 peptides), caerulein-precursor fragments, CPF (4 peptides), and xenopsin-precursor fragments, XPF (2 peptides), previously isolated from Xenopus laevis and X. amieti. In addition, a second magainin-related peptide (G**KFLHSAGKFGKAFLGEVMIG) containing a two amino acid residue deletion compared with magainin-2 was identified that had only weak antimicrobial activity. The peptide with the greatest potential for development into a therapeutically valuable anti-infective agent was CPF-B1 (GLGSLLGKAFKIGLKTVGKMMGGAPREQ) with MIC = 5 μM against E. coli, MIC = 5 μM against S. aureus, and MIC = 25 μM against Candida albicans, and low hemolytic activity against human erythrocytes (LC50 > 200 μM). This peptide was also the most abundant antimicrobial peptide in the skin secretions. CPF-B1 was active against clinical isolates of the nosocomial pathogens, methicillin-resistant S. aureus (MRSA) and multidrug-resistant Acinetobacter baumannii (MDRAB) with MIC values in the range 4–8 μM.
The emergence of multidrug-resistant strains of Acinetobacter baumannii (MDRAB) constitutes a ser... more 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).▶ 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.
Comparative Biochemistry and Physiology C-toxicology & Pharmacology, 2010
Nine peptides with differential growth inhibitory activity against Escherichia coli and Staphyloc... more Nine peptides with differential growth inhibitory activity against Escherichia coli and Staphylococcus aureus were isolated from norepinephrine-stimulated skin secretions of the tetraploid frog Xenopus borealis Parker, 1936 (Pipidae). Structural characterization of the peptides demonstrated that they were orthologous to magainin-2 (1 peptide), peptide glycine–leucine-amide, PGLa (2 peptides), caerulein-precursor fragments, CPF (4 peptides), and xenopsin-precursor fragments, XPF (2 peptides), previously isolated from Xenopus laevis and X. amieti. In addition, a second magainin-related peptide (G**KFLHSAGKFGKAFLGEVMIG) containing a two amino acid residue deletion compared with magainin-2 was identified that had only weak antimicrobial activity. The peptide with the greatest potential for development into a therapeutically valuable anti-infective agent was CPF-B1 (GLGSLLGKAFKIGLKTVGKMMGGAPREQ) with MIC = 5 μM against E. coli, MIC = 5 μM against S. aureus, and MIC = 25 μM against Candida albicans, and low hemolytic activity against human erythrocytes (LC50 > 200 μM). This peptide was also the most abundant antimicrobial peptide in the skin secretions. CPF-B1 was active against clinical isolates of the nosocomial pathogens, methicillin-resistant S. aureus (MRSA) and multidrug-resistant Acinetobacter baumannii (MDRAB) with MIC values in the range 4–8 μM.
ABSTRACT New nicotinic acid derivatives (IV) display distinctive analgesic and antiinflammatory a... more ABSTRACT New nicotinic acid derivatives (IV) display distinctive analgesic and antiinflammatory activities in comparison to mefenamic acid as reference drug.
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