Lysin-antimicrobial peptide (amp) polypeptide constructs, lysins, isolated polynucleotides encoding same and uses thereof

Abstract

The present disclosure is directed to a lysin-AMP polypeptide construct comprising: (a) a first component comprising the polypeptide sequence of: (i) SEQ ID NO: 118 (GN202); or (ii) a polypeptide having lysin activity and having at least 80% sequence identity with the polypeptide sequence of SEQ ID NO: 118 (GN202); or (iii) an active fragment of SEQ ID NO: 118 (GN202); and (b) a second component comprising the polypeptide sequence of at least one antimicrobial peptide (AMP), wherein the at least one AMP comprises SEQ ID NO: 114 (FIRL). Exemplary lysin-AMP polypeptides, such as GN370 (SEQ ID NO: 44) as well as methods of treating bacterial infections using the present lysin-AMP polypeptide constructs are also disclosed.

1 .- 19 . (canceled) 
     
     
         20 . A method of treating a bacterial infection caused by a Gram-negative bacteria, wherein the Gram-negative bacteria is an extensively antibiotic-resistant (XDR) bacteria, which method comprises:
 administering to a subject diagnosed with, at risk for, or exhibiting symptoms of a bacterial infection, a pharmaceutical composition comprising a lysin-AMP polypeptide construct comprising:
 (a) a first component comprising the polypeptide sequence of:
 (i) SEQ ID NO: 118 (GN202); or 
 (ii) a polypeptide having lytic activity and having at least 80% sequence identity with the polypeptide sequence of SEQ ID NO: 118 (GN202); or 
 (iii) an active fragment of SEQ ID NO: 118 (GN202); and 
 
 (b) a second component comprising the polypeptide sequence of at least one antimicrobial peptide (AMP), wherein the at least one AMP comprises the polypeptide sequence of SEQ ID NO: 114 (FIRL). 
   
     
     
         21 . The method according to  claim 20 , wherein the lysin-AMP polypeptide construct comprises the polypeptide sequence of SEQ ID NO: 44 (GN370). 
     
     
         22 . The method according to  claim 20 , wherein the bacterial infection is a topical bacterial infection. 
     
     
         23 . The method according to  claim 20 , wherein the Gram-negative bacteria is  Pseudomonas aeruginosa.    
     
     
         24 . The method according to  claim 20 , wherein the Gram-negative bacteria is selected from the group consisting of  Klebsiella pneumoniae, Acinetobacter baumannii, Enterobacter cloacae Escherichia coli, Stentrophomonas maltophilia, Achromobacter  spp., and  Pandorea apista.    
     
     
         25 . The method according to  claim 20 , further comprising administering an antibiotic to the subject. 
     
     
         26 . The method according to  claim 25 , wherein the antibiotic is selected from one or more of ceftazidime, cefepime, cefoperazone, ceftobiprole, ciprofloxacin, levofloxacin, aminoglycosides, imipenem, meropenem, doripenem, gentamicin, tobramycin, amikacin, piperacillin, ticarcillin, penicillin, rifampicin, polymyxin B, and colistin. 
     
     
         27 . The method of  claim 20 , wherein the bacterial infection caused by a Gram-negative bacteria is a bacterial infection of an organ or tissue in which pulmonary surfactant is present. 
     
     
         28 . The method of  claim 20 , wherein the bacterial infection comprises pneumonia. 
     
     
         29 . A method of preventing, disrupting or eradicating a Gram-negative bacterial biofilm, wherein the Gram-negative bacteria is an extensively antibiotic-resistant (XDR) bacteria, the method comprising:
 administering a lysin-AMP polypeptide construct comprising:
 (a) a first component comprising the polypeptide sequence of:
 (i) SEQ ID NO: 118 (GN202); or 
 (ii) a polypeptide having lytic activity and having at least 80% sequence identity with the polypeptide sequence of SEQ ID NO: 118 (GN202); or 
 (iii) an active fragment of SEQ ID NO: 118 (GN202); and 
 
 (b) a second component comprising the polypeptide sequence of at least one antimicrobial peptide (AMP), wherein the at least one AMP comprises the polypeptide sequence of SEQ ID NO: 114 (FIRL) in an amount effective to kill Gram-negative bacteria in a biofilm to a subject in need thereof. 
   
     
     
         30 . The method according to  claim 29 , wherein the lysin-AMP construct comprises the polypeptide sequence of SEQ ID NO: 44 (GN370).