Bacteriophage compositions for treating staphylococcus infection

Abstract

The present disclosure relates to bacteriophages and compositions capable of infecting and killing Staphylococcus, and use of the same for treating Staphylococcus, e.g. Staphylococcus aureus, bacterial infections.

1 . An isolated, purified bacteriophage comprising a polynucleotide sequence of SEQ ID NO: 1. 
     
     
         2 . An isolated, purified bacteriophage comprising a polynucleotide sequence with at least 90% identity to SEQ ID NO: 1. 
     
     
         3 . An isolated, purified bacteriophage comprising a polynucleotide sequence of SEQ ID NO: 2. 
     
     
         4 . An isolated, purified bacteriophage comprising a polynucleotide sequence with at least 90% identity to SEQ ID NO: 2. 
     
     
         5 . The bacteriophage of  claim 1 , wherein the bacteriophage is resistant to blood complement inactivation. 
     
     
         6 . A bacteriophage composition comprising one or more bacteriophage selected from a bacteriophage comprising a polynucleotide sequence of SEQ ID NO: 1, SEQ ID NO: 2, a polynucleotide sequence with at least 90% identity to SEQ ID NO: 1, and a polynucleotide sequence with at least 90% identity to SEQ ID NO: 2. 
     
     
         7 . The bacteriophage composition of  claim 6 , comprising two or more of the bacteriophage selected from the bacteriophage comprising a polynucleotide sequence of SEQ ID NO: 1, SEQ ID NO: 2, a polynucleotide sequence with at least 90% identity to SEQ ID NO: 1, and a polynucleotide sequence with at least 90% identity to SEQ ID NO: 2; and wherein the composition's target bacteria range is more effective than the sum of the efficacy of individual bacteriophages in the composition. 
     
     
         8 . The bacteriophage composition of  claim 6 , wherein the bacteriophage infect and kill  Staphylococcus aureus.    
     
     
         9 . The bacteriophage composition of  claim 6 , further comprising a storage media for storage at a temperature at or below 8° C. 
     
     
         10 . The bacteriophage composition of  claim 6 , wherein the bacteriophage is resistant to blood complement inactivation. 
     
     
         11 . The bacteriophage composition of  claim 6 , wherein the one or more bacteriophage belong to the genus Silviavirus. 
     
     
         12 . The composition of  claim 6 , wherein the composition comprises a bacteriophage comprising a polynucleotide sequence with at least 90% identity to SEQ ID NO: 1. 
     
     
         13 . The composition of  claim 6 , wherein the composition comprises a bacteriophage comprising the polynucleotide sequence of SEQ ID NO: 1. 
     
     
         14 . The composition of  claim 6 , wherein the composition comprises a bacteriophage comprising a polynucleotide sequence with at least 90% identity to SEQ ID NO: 2. 
     
     
         15 . The composition of  claim 6 , wherein the composition comprises a bacteriophage comprising the polynucleotide sequence of SEQ ID NO: 2. 
     
     
         16 . The composition of  claim 6 , wherein the composition comprises a bacteriophage comprising a polynucleotide sequence with at least 90% identity to SEQ ID NO: 1 and a polynucleotide sequence with at least 90% identity to SEQ ID NO: 2. 
     
     
         17 . The composition of  claim 6 , wherein the composition comprises a bacteriophage comprising the polynucleotide sequence of SEQ ID NO: 1 and a bacteriophage having a genome comprising the polynucleotide sequence of SEQ ID NO: 2. 
     
     
         18 . The bacteriophage composition of  claim 6 , wherein the composition is substantially free of a bacterial component. 
     
     
         19 . The composition of  claim 18 , wherein the bacterial component comprises bacterial host protein. 
     
     
         20 . The composition of  claim 6 , wherein the composition further comprises a pharmaceutically acceptable carrier, diluent, excipient or combinations thereof. 
     
     
         21 . The composition of  claim 6 , wherein the composition is a liquid, semi-liquid, solid, frozen, or lyophilized formulation. 
     
     
         22 . The composition of  claim 6 , wherein the bacteriophages of the composition target one or more of vancomycin-intermediate  Staphylococcus aureus  (VISA), vancomycin-resistant  Staphylococcus aureus  (VRSA), methicillin-resistant (MRSA)  Staphylococcus aureus.    
     
     
         23 . The composition of  claim 22 , wherein the bacteriophages infect and kill one or more of vancomycin-intermediate  Staphylococcus aureus  (VISA), vancomycin-resistant  Staphylococcus aureus  (VRSA), methicillin-resistant  Staphylococcus aureus  (MRSA). 
     
     
         24 . The composition of  claim 6 , wherein the composition comprises between 1×10 8  and 1×10 11  PFU of each bacteriophage. 
     
     
         25 . The composition of  claim 6 , wherein the composition is to be administered at a dosage of at least 1×10 9  PFU of total bacteriophages per milliliter. 
     
     
         26 . The composition of  claim 6 , wherein the composition is stored at 2-8° C. 
     
     
         27 . The composition of  claim 6 , wherein at least one bacteriophage is obligately lytic. 
     
     
         28 . The bacteriophage or composition of  claim 6 , wherein the sequence of at least one bacteriophage is genetically modified. 
     
     
         29 . A method of treating a bacterial infection comprising administering the bacteriophage or composition of  claim 6  to a subject in need of treatment. 
     
     
         30 . Use of a composition according to  claim 6  in the treatment of a  S. aureus  infection in a subject, the use comprising administering the composition to a subject suffering from a  S. aureus  infection. 
     
     
         31 . Use of a composition comprising one or more distinct bacteriophages that target  Staphylococcus aureus  in the treatment of a subject with a  Staphylococcus aureus  bacterial infection comprising administering the composition to said subject; wherein at least one of said one or more bacteriophages is selected from a bacteriophage comprising a polynucleotide sequence of SEQ ID NO: 1, SEQ ID NO: 2, a polynucleotide sequence with at least 90% identity to SEQ ID NO: 1, and a polynucleotide sequence with at least 90% identity to SEQ ID NO: 2. 
     
     
         32 . The use of  claim 31 , wherein the bacteriophage is resistant to blood complement inactivation. 
     
     
         33 . A bacterial host manufacturing strain comprising a bacteriophage wherein said bacteriophage comprises a polynucleotide sequence selected from SEQ ID NO: 1, SEQ ID NO: 2, a polynucleotide sequence with at least 90% identity to SEQ ID NO: 1, and a polynucleotide sequence with at least 90% identity to SEQ ID NO: 2. 
     
     
         34 . A method of treating a subject with a bacterial infection comprising selecting a bacteriophage based upon resistance to blood complement inactivation and administering said bacteriophage to the subject. 
     
     
         35 . The method of  claim 34 , comprising selecting a bacteriophage based upon resistance to complement C3 protein-mediated inactivation. 
     
     
         36 . The method of  claim 34 , wherein the bacteriophage comprises a polynucleotide sequence selected from SEQ ID NO: 1, SEQ ID NO: 2, a polynucleotide sequence with at least 90% identity to SEQ ID NO: 1, and a polynucleotide sequence with at least 90% identity to SEQ ID NO: 2. 
     
     
         37 . A method of treating a subject with a bacterial infection comprising administering to the subject one or more distinct bacteriophages selected from a bacteriophage comprising a polynucleotide sequence selected from SEQ ID NO: 1, SEQ ID NO: 2, a polynucleotide sequence with at least 90% identity to SEQ ID NO: 1, and a polynucleotide sequence with at least 90% identity to SEQ ID NO: 2. 
     
     
         38 . The method of  claim 37 , wherein the bacterial infection is at least partially due to  Staphylococcus aureus.    
     
     
         39 . The method of  claim 38 , wherein the one or more distinct bacteriophages infect and kill  Staphylococcus aureus.    
     
     
         40 . A method of modifying the microbial flora in a subject comprising administering to said subject at least one bacteriophage that targets  Staphylococcus aureus  bacteria, wherein said bacteriophage comprises a polynucleotide sequence selected from SEQ ID NO: 1, SEQ ID NO: 2, a polynucleotide sequence with at least 90% identity to SEQ ID NO: 1, and a polynucleotide sequence with at least 90% identity to SEQ ID NO: 2. 
     
     
         41 . The method of  claim 37 , wherein the bacteriophage is resistant to blood complement inactivation. 
     
     
         42 . The method of  claim 37 , wherein the one or more phage are selected based upon resistance to complement C3 protein-mediated inactivation. 
     
     
         43 . The method of  claim 37 , wherein the distinct bacteriophage belongs to the genus Silviavirus. 
     
     
         44 . The method of  claim 34 , wherein the bacteriophage comprises a polynucleotide sequence with at least 90% identity to SEQ ID NO: 1. 
     
     
         45 . The method of  claim 34 , wherein the bacteriophage comprises a polynucleotide sequence of SEQ ID NO: 1. 
     
     
         46 . The method of  claim 34 , wherein the bacteriophage comprises a polynucleotide sequence with at least 90% identity to SEQ ID NO: 2. 
     
     
         47 . The method of  claim 34 , wherein the bacteriophage comprises a polynucleotide sequence of SEQ ID NO: 2. 
     
     
         48 . The method of  claim 34 , wherein the bacteriophage comprises a polynucleotide sequence with at least 90% identity to SEQ ID NO: 1 and a bacteriophage comprises a polynucleotide sequence with at least 90% identity to SEQ ID NO: 2. 
     
     
         49 . The method of  claim 34 , wherein the method comprises administering a bacteriophage comprising the polynucleotide sequence of SEQ ID NO: 1 and a bacteriophage comprising the polynucleotide sequence of SEQ ID NO: 2. 
     
     
         50 . The method of  claim 34 , wherein at least about 80% of bacteriophages retain lytic activity after exposure to human plasma for a time period between about 10 minutes and about 120 minutes. 
     
     
         51 . The method of  claim 50 , wherein the time period is between about 10 minutes and about 90 minutes. 
     
     
         52 . The method of  claim 34 , wherein the bacterial infection comprises a pulmonary infection, rhinosinusitis, urinary tract infection, intra-abdominal infection, skin infection, skin structure infection, bacteremia, septicemia, endocarditis, or an implant infection. 
     
     
         53 . The method of  claim 52 , wherein the implant infection comprises a cardiac implant infection (e.g., ventricular assist device infection, pacemaker infection), prosthetic joint infection, or prosthetic valve endocarditis. 
     
     
         54 . The method of  claim 34 , wherein the bacterial infection is bacteremia. 
     
     
         55 . The method of  claim 34 , wherein the bacterial infection is resistant to an antibiotic. 
     
     
         56 . The method of  claim 34 , wherein the bacteriophages are administered at 1×10 8  to 1×10 11  plaque forming units (PFU) of total bacteriophages. 
     
     
         57 . The method of  claim 34 , wherein the bacteriophages are administered at between 1×10 1  and 1×10 11  PFU of each bacteriophage. 
     
     
         58 . The method of  claim 34 , wherein the bacteriophage is administered in a dosage of one milliliter comprising 2×10 9  PFU total bacteriophage. 
     
     
         59 . The method of  claim 34 , wherein the method further comprises administration of an antibiotic. 
     
     
         60 . The method of  claim 59 , wherein the antibiotic is from an antibiotic class selected from the group consisting of a fluoroquinolone, carbapenem, aminoglycoside, ansamycin, cephalosporin, penicillin, beta lactam, beta lactamase inhibitor, folate pathway inhibitor, fucidane, glycopeptide, glycylcycline, lincosamide, lipopeptide, macrolide, oxazolidinone, phenicol phosphonic acid, streptogramin, and tetracycline. 
     
     
         61 . The method of  claim 34 , wherein the bacteriophage is administered intravenously. 
     
     
         62 . The method of  claim 34 , wherein the bacteriophage is administered via intra-articular injection. 
     
     
         63 . The method of  claim 34 , wherein the bacteriophage is administered via inhalation. 
     
     
         64 . The method of  claim 34 , wherein the bacteriophage is administered via nebulization. 
     
     
         65 . The method of  claim 34 , wherein the bacteriophage is administered at least every 6 hours. 
     
     
         66 . The method of  claim 34 , wherein the bacteriophage is administered at least every 12 hours. 
     
     
         67 . The method of  claim 34 , wherein the bacteriophage is administered at least every 24 hours. 
     
     
         68 . The method of  claim 34 , wherein the bacteriophage is administered for at least 7 days. 
     
     
         69 . The method of  claim 34 , wherein the subject is human. 
     
     
         70 . The bacteriophage of  claim 3 , wherein the bacteriophage is resistant to blood complement inactivation.