Novel antimicrobial agents

Abstract

A novel class of antimicrobial polymeric agents, which include a plurality of amino acid residues, such as positively charged amino acid residues, and at least one hydrophobic residue linking therebetween, such as an omega-amino-fatty acid residue, designed to exert antimicrobial activity while being stable, non-toxic and avoiding development of resistance thereto and a process of preparing same are disclosed. Further disclosed are pharmaceutical compositions containing same and a method of treating medical conditions associated with pathological microorganisms, a medical device, an imaging probe and a food preservative utilizing same. Further disclosed are conjugates of an amino acid residue and a hydrophobic moiety residue and a process of preparing same.

1 . A polymer comprising from 2 to 50 units covalently linked to one another via a peptide bond, each unit being either a lysine residue or a conjugate of an ω-amino-fatty acid residue covalently linked to a lysine residue via a peptide bond, at least two of said units being said conjugate, wherein an N-terminus of the polymer is selected from the group consisting of a lysine residue, an ω-amino-fatty acid residue linked via a peptide bond to a lysine residue and a fatty acid residue linked via a peptide bond to a lysine residue. 
     
     
         2 . The polymer of  claim 1 , having a microorganism cell membrane binding activity. 
     
     
         3 . The polymer of  claim 2 , wherein said microorganism is selected from the group consisting of a prokaryotic organism, an  eubacterium , an archaebacterium, a eukaryotic organism, a yeast, a fungus, an alga, a protozon and a parasite. 
     
     
         4 . The polymer of  claim 1 , wherein an N-terminus of the polymer is said fatty acid residue linked via a peptide bond to said lysine residue. 
     
     
         5 . The polymer of  claim 1 , further comprising at least one fatty acid residue linked to the side-chain of a lysine residue of said units. 
     
     
         6 . The polymer of  claim 1 , wherein said ω-amino-fatty acid residue is selected from the group consisting of 4-amino-butyric acid residue, 6-amino-caproic acid residue, 8-amino-caprylic acid residue, 10-amino-capric acid residue, 12-amino-lauric acid residue, 14-amino-myristic acid residue, 16-amino-palmitic acid residue, 18-amino-stearic acid residue, 18-amino-oleic acid residue, 16-amino-palmitoleic acid residue, 18-amino-linoleic acid residue, 18-amino-linolenic acid residue and 20-amino-arachidonic acid residue. 
     
     
         7 . The polymer of  claim 6 , wherein said ω-amino-fatty acid residue is selected from the group consisting of 4-amino-butyric acid residue, 8-amino-caprylic acid residue and 12-amino-lauric acid residue. 
     
     
         8 . The polymer of  claim 1 , further comprising at least one active agent attached thereto. 
     
     
         9 . The polymer of  claim 8 , wherein said at least one active agent is a labeling agent. 
     
     
         10 . The polymer of  claim 9 , wherein said labeling agent is selected from the group consisting of a fluorescent agent, a radioactive agent, a magnetic agent, a chromophore, a phosphorescent agent and a heavy metal cluster. 
     
     
         11 . The polymer of  claim 8 , wherein said at least one active agent comprises at least one therapeutically active agent. 
     
     
         12 . The polymer of  claim 11 , wherein said at least one therapeutically active agent is selected from the group consisting of an agonist residue, an amino acid residue, an analgesic residue, an antagonist residue, an antibiotic agent residue, an antibody residue, an antidepressant agent, an antigen residue, an anti-histamine residue, an anti-hypertensive agent, an anti-inflammatory drug residue, an anti-metabolic agent residue, an antimicrobial agent residue, an antioxidant residue, an anti-proliferative drug residue, an antisense residue, a chemotherapeutic drug residue, a co-factor residue, a cytokine residue, a drug residue, an enzyme residue, a growth factor residue, a heparin residue, a hormone residue, an immunoglobulin residue, an inhibitor residue, a ligand residue, a nucleic acid residue, an oligonucleotide residue, a peptide residue, a phospholipid residue, a prostaglandin residue, a protein residue, a toxin residue, a vitamin residue and any combination thereof. 
     
     
         13 . The polymer of  claim 8 , being capable of delivering at least one active agent to at least a portion of the cells of a pathogenic microorganism. 
     
     
         14 . The polymer of  claim 13 , wherein said pathogenic microorganism is selected from the group consisting of a prokaryotic organism, an  eubacterium , an archaebacterium, a eukaryotic organism, a yeast, a fungus, an alga, a protozon and a parasite. 
     
     
         15 . The polymer of  claim 13 , wherein said at least one active agent is a labeling agent. 
     
     
         16 . The polymer of  claim 13 , wherein said at least one active agent comprises at least one therapeutically active agent. 
     
     
         17 . A polymer having the general formula I:
   X—W 0 -[A 1 -Z 1 -D 1 ]-W 1 -[A 2 -Z 2 -D 2 ]-W 2 — . . . [An-Zn-Dn]-Wn-Y  Formula I
   wherein:   n is an integer from 2 to 50;   A 1 , A 2 , . . . , An are each a lysine residue;   D 1 , D 2 , . . . , Dn are each independently an ω-amino-fatty acid residue or absent, provided that at least two of said D 1 , D 2 , . . . , Dn is said ω-amino-fatty acid residue;   Z 1 , Z 2 , . . . , Zn and W 0 , W 1 , W 2 , . . . , Wn are each a peptide bond or absent;   X and Y are each independently selected from the group consisting of hydrogen, amine, a lysine residue, a fatty acid residue and an ω-amino-fatty acid residue.   
     
     
         18 . The polymer of  claim 17 , having a microorganism cell membrane binding activity. 
     
     
         19 . The polymer of  claim 18 , being capable of selectively destructing at least a portion of the cells of a pathogenic microorganism. 
     
     
         20 . The polymer of  claim 19 , wherein said pathogenic microorganism is selected from the group consisting of a prokaryotic organism, an  eubacterium , an archaebacterium, a eukaryotic organism, a yeast, a fungus, an alga, a protozon and a parasite. 
     
     
         21 . The polymer of  claim 17 , wherein X is a fatty acid residue or an ω-amino-fatty acid residue. 
     
     
         22 . The polymer of  claim 17 , wherein Y is an ω-amino-fatty acid residue. 
     
     
         23 . The polymer of  claim 17 , wherein at least one of said lysine residues has a fatty acid residue attached to a side chain thereof. 
     
     
         24 . The polymer of  claim 17 , wherein each of said ω-amino-fatty acid residues is independently selected from the group consisting of 4-amino-butyric acid, 6-amino-caproic acid, 8-amino-caprylic acid, 10-amino-capric acid, 12-amino-lauric acid, 14-amino-myristic acid, 16-amino-palmitic acid, 18-amino-stearic acid, 18-amino-oleic acid, 16-amino-palmitoleic acid, 18-amino-linoleic acid, 18-amino-linolenic acid and 20-amino-arachidonic acid. 
     
     
         25 . The polymer of  claim 17 , further comprising at least one active agent attached thereto. 
     
     
         26 . The polymer of  claim 25 , wherein said at least one active agent is a labeling agent. 
     
     
         27 . The polymer of  claim 25 , wherein said at least one active agent comprises at least one therapeutically active agent. 
     
     
         28 . A pharmaceutical composition comprising, as an active ingredient, the polymer of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         29 . An imaging probe for detecting a pathogenic microorganism, the imaging probe comprising a polymer, said polymer includes a plurality of amino acid residues and at least one hydrophobic moiety residue, wherein at least one of said at least one hydrophobic moiety residue is being covalently linked to at least two amino acid residues in said plurality of amino acid residues via the N-alpha of one amino acid residue and via the C-alpha of the other amino acid residue in said at least two amino acid residues, whereas said polymer further includes at least one labeling agent attached thereto. 
     
     
         30 . The imaging probe of  claim 29 , wherein said at least one labeling agent is attached to a side chain of at least one amino acid residue of said plurality of amino acid residues in said polymer. 
     
     
         31 . The imaging probe of  claim 29 , wherein said at least one labeling agent is attached to the C-terminus and/or the N-terminus of said plurality of amino acid residues in said polymer. 
     
     
         32 . The imaging probe of  claim 29 , wherein said at least one labeling agent is attached to at least one of said at least one hydrophobic moiety residue in said polymer. 
     
     
         33 . The imaging probe of  claim 29 , wherein said at least one labeling agent is selected from the group consisting of a chromophore, a fluorescent agent, a phosphorescent agent, a heavy metal cluster and a radioactive agent. 
     
     
         34 . A pharmaceutical composition comprising, as an active ingredient, the polymer of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         35 . The pharmaceutical composition of  claim 34 , being packaged in a packaging material and identified in print, in or on said packaging material, for use in the treatment of a medical condition associated with a pathogenic microorganism. 
     
     
         36 . The pharmaceutical composition of  claim 35 , wherein said pathogenic microorganism is selected from the group consisting of a prokaryotic organism, an  eubacterium , an archaebacterium, a eukaryotic organism, a yeast, a fungus, an alga, a protozon and a parasite. 
     
     
         37 . The pharmaceutical composition of  claim 34 , further comprising at least one additional therapeutically active agent. 
     
     
         38 . The pharmaceutical composition of  claim 37 , wherein said at least one additional therapeutically active agent comprises an antibiotic agent. 
     
     
         39 . A method of treating a medical condition associated with a pathogenic microorganism, the method comprising administering to a subject in need thereof a therapeutically effective amount of the polymer of  claim 1 . 
     
     
         40 . The method of  claim 39 , wherein said pathogenic microorganism is selected from the group consisting of a prokaryotic organism, an  eubacterium , an archaebacterium, a eukaryotic organism, a yeast, a fungus, an alga, a protozon and a parasite. 
     
     
         41 . The method of  claim 39 , further comprising administering to said subject at least one therapeutically active agent. 
     
     
         42 . The method of  claim 41 , wherein said at least one therapeutically active agent comprises an antibiotic agent. 
     
     
         43 . A medical device comprising the polymer of  claim 1  and a delivery system configured for delivering said polymer to a bodily site of a subject. 
     
     
         44 . A food preservative comprising an effective amount of the polymer of  claim 1 . 
     
     
         45 . The food preservative of  claim 44 , further comprising an edible carrier.