Compositions, methods and uses for treating bacterial infections

Abstract

A novel method of treating and preventing bacterial diseases is provided. In particular, the present invention relates to compositions and methods for inhibition of Gram negative, Gram positive and acid fast bacilli in general and tuberculosis (TB), mycobacterium avium complex (MAC), and anthrax in particular. Thus, the invention relates to modulation of cellular activities, including macrophage activity, and the like. More particularly, the present invention relates to the inhibitory compounds comprising naturally occurring and man-made inhibitors of serine protease.

1 . A method for treating a bacterial infection in a subject comprising: administering a therapeutically effective amount of a composition comprising mammalian α1-antitrypsin or fragment thereof, the α1-antitrypsin comprises naturally occurring α1-antitrypsin, and treating the subject for the bacterial infection. 
     
     
         2 . The method of  claim 1 , wherein the naturally occurring α1-antitrypsin is not a mutant form of α1-antitrypsin. 
     
     
         3 . The method of  claim 1 , wherein the composition comprising a mammalian α1-antitrypsin is a pharmaceutical composition comprising SEQ ID NO:61 or fragment thereof to the subject. 
     
     
         4 . The method of  claim 1 , wherein the fragment comprises one or more peptide selected from the group consisting of FVFLM (SEQUENCE ID NO. 1), or analog of FVFLM, FVFAM (SEQUENCE ID NO. 2), FVALM (SEQUENCE ID NO. 3), FVFLA (SEQUENCE ID NO. 4), FLVFI (SEQUENCE ID NO. 5), FLMII (SEQUENCE ID NO. 6), FLFVL (SEQUENCE ID NO. 7), FLFVV (SEQUENCE ID NO. 8), FLFLI (SEQUENCE ID NO. 9), FLFFI (SEQUENCE ID NO. 10), FLMFI (SEQUENCE ID NO. 11), FMLLI (SEQUENCE ID NO. 12), FIIMI (SEQUENCE ID NO. 13), FLFCI (SEQUENCE ID NO. 14), FLFAV (SEQUENCE ID) NO. 15), FVYLI (SEQUENCE ID NO. 16), FAFLM (SEQUENCE ID NO. 17), AVFLM (SEQUENCE ID NO. 18), and a combination thereof. 
     
     
         5 . The method of  claim 1 , wherein the mammalian α1-antitrypsin comprises Aralast™ (Baxter), Zemaira™ (Aventis Behring), Prolastin™ (Bayer), or a combination thereof. 
     
     
         6 . The method of  claim 1 , wherein the bacterial infection is caused by one or more gram negative bacteria. 
     
     
         7 . The method of  claim 1 , wherein the bacterial infection is caused by one or more gram positive bacteria. 
     
     
         8 . The method of  claim 1 , wherein administration comprises continuous infusion to provide 0.01 to 5.0 mg/kg of α1-antitrypsin to the subject. 
     
     
         9 . The method of  claim 1 , wherein administration comprises intermittent infusions comprising about 0.4 to 20 mg/kg of α1-antitrypsin to the subject. 
     
     
         10 . The method of  claim 1 , further comprising administering at least one additional anti-bacterial agent to the subject. 
     
     
         11 . A method for treating a bacterial infection in a subject comprising: administering a therapeutically effective amount of a composition comprising mammalian α1-antitrypsin or fragment thereof, the α1-antitrypsin is naturally occurring α1-antitrypsin and does not have furin endoprotease inhibitory activity; and treating the subject for the bacterial infection. 
     
     
         12 . The method of  claim 11 , wherein the fragment comprises one or more peptide selected from the group consisting of FVFLM (SEQUENCE ID NO. 1), or analog of FVFLM, FVFAM (SEQUENCE ID NO. 2), FVALM (SEQUENCE ID NO. 3), FVFLA (SEQUENCE ID NO. 4), FLVFI (SEQUENCE ID NO. 5), FLMII (SEQUENCE ID NO. 6), FLFVL (SEQUENCE ID NO. 7), FLFVV (SEQUENCE ID NO. 8), FLFLI (SEQUENCE ID NO. 9), FLFFI (SEQUENCE ID NO. 10), FLMFI (SEQUENCE ID NO. 11), FMLLI (SEQUENCE ID NO. 12), FIIMI (SEQUENCE ID NO. 13), FLFCI (SEQUENCE ID NO. 14), FLFAV (SEQUENCE ID) NO. 15), FVYLI (SEQUENCE ID NO. 16), FAFLM (SEQUENCE ID NO. 17), AVFLM (SEQUENCE ID NO. 18), and a combination thereof. 
     
     
         13 . The method of  claim 11 , wherein the mammalian α1-antitrypsin comprises Aralast™ (Baxter), Zemaira™ (Aventis Behring), Prolastin™ (Bayer), or a combination thereof. 
     
     
         14 . A method of treating a subject exposed or suspected of being exposed to a pathogenic bacteria comprising, administering to the subject a pharmaceutically effective amount of mammalian α1-antitrypsin or fragment thereof, the α1-antitrypsin or fragment thereof inhibits endogenous host protease cell-surface processing of inactive large PA into active smaller PA molecule; and treating the subject for the bacterial infection. 
     
     
         15 . The method of  claim 14 , wherein the α1-antitrypsin or fragment thereof comprises a protein or peptide having Ala-Ile-Pro-Met corresponding to amino acids 355-358 of SEQ ID NO: 61. 
     
     
         16 . A method for prolactically treating a subject for one or more bacterial infection(s) in a subject comprising: administering a therapeutically effective amount of a composition comprising mammalian α1-antitrypsin or fragment thereof, the α1-antitrypsin comprises naturally occurring α1-antitrypsin, and prolactically treating the subject for the bacterial infection. 
     
     
         17 . A composition comprising, a peptide comprising AGAMFLEAIP (SEQUENCE ID NO. 56); MSIPPEVKFN (SEQUENCE ID NO. 57); KPFVFLMIEQ (SEQUENCE ID NO. 58); NTKSPLFMGK (SEQUENCE ID NO. 59); VVNPTQK (SEQUENCE ID NO. 60), and a combination thereof. 
     
     
         18 . The composition of  claim 17  comprising, AGAMFLEAIP (SEQUENCE ID NO. 56); MSIPPEVKFN (SEQUENCE ID NO. 57); KPFVFLMIEQ (SEQUENCE ID NO. 58); and a combination thereof. 
     
     
         19 . The composition of  claim 17 , wherein the composition comprises fusion polypeptides.