Composition with high antimicrobial activity and low toxicity

Abstract

Improved synthetic copolypeptide antimicrobials contain cationic amino acid residues and may be based on a blocky sequence. These antimicrobials show low mammalian toxicity and may undergo directed self-assembly. The inventive synthetic copolypeptides are useful in treatment of wounds and other infections.

1 . An antimicrobial composition comprising:
 water and one or more hierarchical structures comprising at least one species of synthetic polypeptide, wherein:
 said at least one species of synthetic polypeptide comprises at least forty amino acid residues; 
 said at least one species of synthetic polypeptide comprises a plurality of cationic amino acid residues and a plurality of hydrophobic amino acid residues; 
 said at least one species of synthetic polypeptide has a net positive charge at neutral pH; 
 said at least one species of synthetic polypeptide demonstrates a critical aggregation concentration below that of a random-sequence polypeptide of the same amino acid composition; 
 said at least one species of synthetic polypeptide inhibits or kills microbes; and 
 said antimicrobial composition inhibits or kills microbes. 
   
     
     
         2 - 20 . (canceled) 
     
     
         21 . The antimicrobial composition of  claim 1 , wherein said one or more hierarchical structures is selected from multimers, micelles, fibrils, sheets, and vesicles, or mixtures thereof. 
     
     
         22 . The antimicrobial composition of  claim 1 , wherein said plurality of cationic amino acid residues comprises amino acid residues selected from lysine, arginine, homoarginine and ornithine. 
     
     
         23 . The antimicrobial composition of  claim 1 , wherein said plurality of hydrophobic amino acid residues are selected from leucine, valine, phenylalanine, isoleucine and alanine. 
     
     
         24 . The antimicrobial composition of  claim 1 , wherein the molar fraction of hydrophobic amino acid residues in said at least one species of synthetic polypeptide is 40% or less. 
     
     
         25 . The antimicrobial composition of  claim 1 , wherein said at least one species of synthetic polypeptide comprises at least five cationic amino acid residues. 
     
     
         26 . The antimicrobial composition of  claim 1 , wherein said at least one species of synthetic polypeptide has a critical aggregation concentration that is at least 20% lower than that of a random sequence polypeptide having the same amino acid residue composition as said at least one species of synthetic polypeptide. 
     
     
         27 . The antimicrobial composition of  claim 1 , wherein said at least one species of synthetic polypeptide has a critical aggregation concentration that is at least 1 log lower than that of a random sequence polypeptide having the same amino acid residue composition as said at least one species of synthetic polypeptide. 
     
     
         28 . The antimicrobial composition of  claim 1 , wherein said at least one species of synthetic polypeptide demonstrates a critical aggregation concentration in water of less than 160 μM. 
     
     
         29 . The antimicrobial composition of  claim 1 , wherein said at least one species of synthetic polypeptide is a surfactant. 
     
     
         30 . The antimicrobial composition of  claim 1 , wherein said at least one species of synthetic polypeptide is a surfactant, as measured by a decrease in surface tension. 
     
     
         31 . The antimicrobial composition of  claim 1 , wherein said at least one species of synthetic polypeptide forms emulsions when mixed with oil and water. 
     
     
         32 . The antimicrobial composition of  claim 1 , wherein said at least one species of synthetic polypeptide forms a hydrogel in water at a concentration of 40 mg/mL or less. 
     
     
         33 . The antimicrobial composition of  claim 1 , wherein said at least one species of synthetic polypeptide comprises L-amino acid residues, D-amino acid residues, a racemic mixture of L- and D-amino acid residues, or a mixture of varying optical purity of amino acid residues. 
     
     
         34 . The antimicrobial composition of  claim 1 , wherein said at least one species of synthetic polypeptide kills or inhibits microbes in vitro at a lower concentration than the synthetic polypeptide kills mammalian cells in vitro. 
     
     
         35 . The antimicrobial composition of  claim 1 , wherein said at least one species of synthetic polypeptide kills or inhibits microbes in vitro at concentrations below 0.1% (w/w) of the synthetic polypeptide in water. 
     
     
         36 . The antimicrobial composition of  claim 1 , wherein said at least one species of synthetic polypeptide kills or inhibits microbes in vitro as measured by greater than 3 logs killing of  Staphylococcus epidermidis  and  Escherichia coli  in standard 60 minute time-kill assays at synthetic polypeptide concentrations of 100 μg/mL or less in water. 
     
     
         37 . The antimicrobial composition of  claim 1 , wherein the microbes are selected from bacteria, viruses, fungi and protozoans. 
     
     
         38 . The antimicrobial composition of  claim 1 , wherein the antimicrobial composition further comprises an added active pharmaceutical ingredient selected from a steroid, a pro-inflammatory agent, an anti-inflammatory agent, an antiacne agent, a preservative, a hemostatic agent, an angiogenic agent, a wound healing agent, an antibiotic, an antibody, and an anti-cancer agent. 
     
     
         39 . The antimicrobial composition of  claim 1 , wherein the antimicrobial composition is formulated as a solution, a gel, a cream, a foam or a dressing. 
     
     
         40 . The antimicrobial composition of  claim 1 , wherein the antimicrobial composition promotes platelet aggregation. 
     
     
         41 . The antimicrobial composition of  claim 1 , wherein the antimicrobial composition inhibits fibrinolysis. 
     
     
         42 . A method of preventing or treating an infection comprising:
 administering or applying to a site the antimicrobial composition of  claim 1 ;   wherein the infection is selected from topical infection, microbial colonization, wound infection, surgical site infection, trauma infection, burn infection, diabetic foot ulcers, eye infection, vaginal infections, or urinary tract infections.