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 - 27 . (canceled) 
     
     
         28 . A method of treating a  Staphylococcus  bacterial infection in a subject comprising:
 administering to the subject a combination comprising bacteriophage lysin PlySs2 and daptomycin,   wherein the PlySs2 lysin comprises the amino acid sequence of SEQ ID NO: 1 or a variant thereof having at least 80% amino acid identity to SEQ ID NO: 1 and effective to kill the  Staphylococcus  bacteria,   wherein the combination is effective to reduce the minimally-inhibitory concentration (MIC) dose for daptomycin and PlySs2 lysin,   wherein the  Staphylococcus  bacterial infection is in a biological fluid comprising pulmonary surfactant, and   wherein the combination renders daptomycin effective in the presence of pulmonary surfactant and for treatment of pneumonia.   
     
     
         29 . The method of  claim 28 , wherein the bacterial infection is a  Staphylococcus aureus  infection. 
     
     
         30 . The method of  claim 28 , wherein the infection is due to antibiotic-resistant  Staphylococcus  bacteria. 
     
     
         31 . The method of  claim 30 , wherein the bacteria are methicillin-resistant  Staphylococcus aureus  (MRSA). 
     
     
         32 . The method of  claim 30 , wherein the bacteria are vancomycin-resistant  Staphylococcus aureus  (VRSA). 
     
     
         33 . The method of  claim 28 , wherein the subject has pneumonia. 
     
     
         34 . The method of  claim 28 , wherein each of the daptomycin and the PlySs2 lysin are effective in the combination at doses below their MIC dose. 
     
     
         35 . A method of treating a  Streptococcus  bacterial infection in a subject comprising:
 administering to the subject a combination comprising bacteriophage lysin PlySs2 and daptomycin,   wherein the PlySs2 lysin comprises the amino acid sequence of SEQ ID NO: 1 or a variant thereof having at least 80% amino acid identity to SEQ ID NO: 1 and effective to kill the  Streptococcus  bacteria, and   wherein the combination is effective to reduce the minimally-inhibitory concentration (MIC) dose for daptomycin and PlySs2 lysin,   wherein the  Streptococcus  bacterial infection is in a biological fluid comprising pulmonary surfactant, and   wherein the combination renders daptomycin effective in the presence of pulmonary surfactant and for treatment of pneumonia.   
     
     
         36 . The method of  claim 35 , wherein the bacterial infection is a  Streptococcus pneumoniae  infection. 
     
     
         37 . The method of  claim 35 , wherein the bacterial infection is a Group A or Group B  Streptococcus  bacterial infection. 
     
     
         38 . The method of  claim 35 , wherein the infection is due to antibiotic-resistant  Streptococcus  bacteria. 
     
     
         39 . The method of  claim 35 , wherein each of the daptomycin and the PlySs2 lysin are effective in the combination at doses below their MIC dose. 
     
     
         40 . A method of reducing the development of antibiotic-resistant  Staphylococcus  bacteria in a subject with a  Staphylococcus  bacterial infection comprising:
 administering a combination comprising bacteriophage lysin PlySs2 and daptomycin to the subject,   wherein the PlySs2 lysin comprises the amino acid sequence of SEQ ID NO:1 or a variant thereof having at least 80% amino acid identity to SEQ ID NO: 1 and effective to kill the  Staphylococcus  bacteria, and   wherein the combination is effective to reduce the development of antibiotic-resistant gram-positive bacteria and the minimally-inhibitory concentration (MIC) dose for daptomycin and PlySs2 lysin,   wherein the  Staphylococcus  bacterial infection is in a biological fluid comprising pulmonary surfactant, and   wherein the combination renders daptomycin effective in the presence of pulmonary surfactant and for treatment of pneumonia, whereby antibiotic resistance is suppressed relative to administration of daptomycin alone.   
     
     
         41 . The method of  claim 40 , wherein each of the daptomycin and the PlySs2 lysin are effective in the combination at doses below their MIC dose. 
     
     
         42 . The method of  claim 40 , wherein antibiotic-resistant bacteria have increased sensitivity to PlySs2 lysin compared to antibiotic sensitive gram-positive bacteria. 
     
     
         43 . The method of  claim 28 , wherein the bacteriophage lysin PlySs2 and the daptomycin are administered to the subject separately and simultaneously or in series. 
     
     
         44 . The method of  claim 35 , wherein the bacteriophage lysin PlySs2 and the daptomycin are administered to the subject separately and simultaneously or in series. 
     
     
         45 . The method of  claim 40 , wherein the bacteriophage lysin PlySs2 and the daptomycin are administered to the subject separately and simultaneously or in series.