Antimicrobial polymer conjugates

Abstract

Water-soluble polymer conjugates of antimicrobial agents retaining at least a portion of the antimicrobial activity of the agent, pharmaceutical compositions containing the polymer conjugates, and methods for treating microbial infections with the pharmaceutical compositions.

1 . A water-soluble polymer conjugated to lysostaphin such that at least a portion of the antimicrobial activity of said lysostaphin is retained. 
   
   
       2 . The polymer conjugated lysostaphin of  claim 1 , wherein said lysostaphin retains enzyme activity capable of cleaving the cross-linked polyglycine bridges in the cell wall peptidoglycan of Staphylococci. 
   
   
       3 . The polymer conjugated lysostaphin of  claim 2 , wherein said lysostaphin is wild type lysostaphin or a lysostaphin analogue. 
   
   
       4 . The polymer conjugated agent of  claim 3 , wherein said wild type lysostaphin or lysostaphin analogue is recombinantly expressed. 
   
   
       5 . The polymer conjugated lysostaphin of  claim 1 , wherein said water-soluble polymer is selected from the group consisting of poly(alkylene oxides), polyoxyethylated polyols and poly(vinyl alcohols). 
   
   
       6 . The polymer conjugated lysostaphin of  claim 5 , wherein said poly(alkylene oxide) is a polyoxamer or polyoxamine. 
   
   
       7 . The polymer conjugated lysostaphin of  claim 5 , wherein said poly(alkylene oxide) is polyethylene glycol (PEG). 
   
   
       8 . The polymer conjugated lysostaphin of  claim 7 , wherein said PEG is straight-chained. 
   
   
       9 . The polymer conjugated lysostaphin of  claim 7 , wherein said PEG is branched. 
   
   
       10 . The polymer conjugated lysostaphin of  claim 1  comprising from one to about four polymer molecules per molecule of lysostaphin. 
   
   
       11 . An antimicrobial pharmaceutical composition for treating an infection comprising a water-soluble polymer conjugated to lysostaphin such that at least a portion of the antimicrobial activity of said lysostaphin is retained and a pharmaceutically acceptable carrier. 
   
   
       12 . The pharmaceutical composition of  claim 11 , further comprising a non-polymer conjugated antibacterial enzyme. 
   
   
       13 . The pharmaceutical composition of  claim 12 , wherein said non-polymer conjugated antibacterial enzyme is selected from the group consisting of lysostaphin, lysozyme, mutanolysin, cellozyl muramidase, and combinations thereof. 
   
   
       14 . The pharmaceutical composition of  claim 11 , further comprising an antibiotic. 
   
   
       15 . The pharmaceutical composition of  claim 14 , wherein said antibiotic interferes with or inhibits bacterial cell wall synthesis. 
   
   
       16 . The pharmaceutical composition of  claim 14 , wherein said antibiotic is selected from the group consisting of α-lactams, cephalosporins, aminoglycosides, sulfonamides, antifolates, macrolides, quinolones, glycopeptides, polypeptides and combinations thereof. 
   
   
       17 . A method for the prophylactic or therapeutic treatment of a microbial infection in a mammal comprising administering to said mammal an effective amount of a pharmaceutical composition according to  claim 11  for treating said infection. 
   
   
       18 . The method of  claim 17 , wherein said microbial infection is a bacterial infection caused by a  staphylococcus  species with sufficient polyglycine bridge cross-linking in the cell wall peptidoglycan for cells of the species to be lysed by contact with a water-soluble polymer conjugate of lysostaphin. 
   
   
       19 . The method of  claim 18 , wherein said staphylococcal infection is caused by  Staphylococcus aureus.    
   
   
       20 . The method of  claim 18 , wherein said staphylococcal infection is caused by  Staphylococcus epidermidis.