Bacteriophage lysin and antibiotic combinations against gram positive bacteria

Abstract

The present invention provides compositions and methods for prevention, amelioration and treatment of gram positive bacteria, particularly Staphylococcal bacteria, with combinations of lysin, particularly Streptococcal lysin, particularly the lysin PlySs2, and one or more antibiotic, including daptomycin, vancomycin, oxacillin, linezolid, or related antibiotic(s).

1 - 15 . (canceled) 
     
     
         16 . A method of enhancing the effectiveness of a gram-positive antibiotic comprising administering the antibiotic with PlySs2 lysin comprising the amino acid sequence provided in  FIG. 29  (SEQ ID NO: 1) or variants thereof having at least 80% identity, 85% identity, 90% identity, 95% identity or 99% identity to the polypeptide of  FIG. 29  (SEQ ID NO: 1) and effective to kill gram-positive bacteria, whereby the antibiotic is at least 10 fold more effective in combination with Plyss2. 
     
     
         17 . (canceled) 
     
     
         18 . The method of  claim 16  wherein the antibody is at least 50 fold more effective in combination with PlySs2 lysin. 
     
     
         19 . The method of  claim 16  wherein the PlySs2 lysin is at least two fold more effective in combination with antibody. 
     
     
         20 . The method of  claim 16  wherein the PlySs2 lysin is at least four fold more effective in combination with antibody. 
     
     
         21 - 23 . (canceled) 
     
     
         24 . A composition for use in inhibiting gram positive bacteria selected from  Staphylococcus, Streptococcus, Enterococcus  and  Listeria  comprising PlySs2 lysin polypeptide and one or more antibiotic. 
     
     
         25 . The composition of  claim 24  wherein the antibiotic is selected from vancomycin or a related antibiotic, linezolid or a related antibiotic, oxacillin or a related antibiotic and daptomycin or a related antibiotic. 
     
     
         26 . The composition of  claim 24  wherein the antibiotic is daptomycin, vancomycin, oxacillin or linezolid. 
     
     
         27 . The composition of  claim 24  wherein the dose of antibiotic is at least X fold lower than the ordinary clinical dose. 
     
     
         28 . A method of killing  Staphylococcus  and/or  Streptococcus  bacteria comprising:
 contacting the bacteria with a lysin polypeptide in combination with an antibiotic,   wherein the lysin polypeptide is effective to kill  Staphylococcus  and/or  Streptococcus  bacteria, wherein the lysin polypeptide comprises SEQ ID NO: 1 or a variant thereof having at least 80% identity to the amino acid of SEQ ID NO: 1 and effective to kill the one or more of  Staphylococcus  and  Streptococcus  bacteria,   wherein an amount of the lysin polypeptide effective to kill the  Staphylococcus  and/or  Streptococcus  bacteria in the presence of the antibiotic is less than in the absence of the antibiotic, and   wherein an amount of antibiotic effective to kill the  Staphylococcus  and/or the  Streptococcus  bacteria in the presence of the lysin polypeptide is less than in the absence of the lysin polypeptide.   
     
     
         29 . The method of  claim 28 , wherein the antibiotic and the lysin polypeptide are administered sequentially. 
     
     
         30 . The method of  claim 28 , wherein the antibiotic and the lysin polypeptide are administered concurrently. 
     
     
         31 . The method of  claim 28 , wherein the lysin polypeptide is administered in a single dose. 
     
     
         32 . The method of  claim 28 , wherein the lysin polypeptide is administered in multiple doses. 
     
     
         33 . The method of  claim 28 , wherein both the antibiotic and the lysin polypeptide are administered at doses below the minimal inhibitory concentration (MIC) dose. 
     
     
         34 . The method of  claim 28 , wherein a dose of the antibiotic is lower than the minimal inhibitory concentration (MIC) dose. 
     
     
         35 . The method of claim  1 , wherein the antibiotic is a glycopeptide. 
     
     
         36 . The method of  claim 35 , wherein the glycopeptide is vancomycin. 
     
     
         37 . The method of claim  1 , wherein the antibiotic is a lipopeptide. 
     
     
         38 . The method of  claim 37 , wherein the lipopeptide is daptomycin. 
     
     
         39 . The method of claim  1 , wherein the antibiotic is a beta lactam penicillin. 
     
     
         40 . The method of  claim 39 , wherein the beta lactam penicillin is penicillin. 
     
     
         41 . The method of claim  1 , wherein the antibiotic is an oxazolidinone. 
     
     
         42 . The method of  claim 41 , wherein the oxazolidinone is linezolid. 
     
     
         43 . The method of  claim 28 , wherein the  Staphylococcus  bacteria comprise  Staphylococcus aureus.    
     
     
         44 . The method of  claim 43 , wherein the  Staphylococcus aureus  is methicillin resistant  Staphylococcus aureus  (MRSA). 
     
     
         45 . The method of  claim 28 , wherein the PlySs2 binding domain variant has at least 90% identity to the amino acid sequence of SEQ ID NO: 1. 
     
     
         46 . The method of  claim 28 , wherein the PlySs2 binding domain comprises SEQ ID NO: 1. 
     
     
         47 . The method of  claim 28 , wherein the lysin polypeptide and the antibiotic are administered to a subject having bacteremia.