Compositions and methods for treating or ameliorating mycobacterial 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 poitive 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 disorder caused by  Mycobacterium  in a subject comprising: administering a therapeutically effective amount of a composition comprising mammalian α1-antitrypsin or derivative thereof to the subject. 
     
     
         2 . The method of  claim 1 , wherein the  Mycobacterium  comprises one of more of  Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium leprae, Mycobacterium chelonei, Mycobacterium africanum, Mycobacterium marinium, Mycoburuli, Mycobacterium fortuitum, Mycobacterium haemophilum, Mycobacterium intracellulare, Mycobacterium kansasii, Mycobacterium littorale, Mycobacterium malmoense, Mycobacterium marianum, Mycobacterium simiae, Mycobacterium szulgai, Mycobacterium ulceranis, Mycobacterium avium, Mycobacterium flavascens, Mycobacterium lepraemurium, Mycobacterium microti, Mycobacterium paratuberculosis, Mycobacterium scrofulaceum, Mycobacterium xenopi, Mycobacterium gordonae, Mycobacterium genavense, Mycobacterium  abscessus other  Mycobacterium  or a combination thereof. 
     
     
         3 . The method of  claim 1 , wherein the  Mycobacterium  is  Mycobacterium tuberculosis  or  Mycobacterium bovis.    
     
     
         4 . The method of  claim 3 , wherein the disorder comprises acute or chronic disease caused by infection with  Mycobacterium tuberculosis  or  Mycobacterium bovis.    
     
     
         5 . The method of  claim 1 , further comprising administering at least one additional anti-bacterial agent to the subject. 
     
     
         6 . The method of  claim 1 , wherein the mycobacterium comprises a member of  Mycobacterium avium  complex (MAC). 
     
     
         7 . The method of  claim 1 , wherein the composition comprising a mammalian α1-antitrypsin is a pharmaceutical composition comprising SEQ ID NO:61. 
     
     
         8 . The method of  claim 1 , wherein the composition comprises one or more peptide derivative of mammalian α1-antitrypsin comprising FVFLM (SEQUENCE ID NO. 1), or derivative 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. 
     
     
         9 . The method of  claim 1 , wherein the composition comprises one or more peptide derivative of mammalian α1-antitrypsin comprising KLSKAVHKAV (SEQUENCE ID NO. 54); LTIDEKGTEA (SEQUENCE ID NO. 55); AGAMFLEAIP (SEQUENCE ID NO. 56); MSIPPEVKFN (SEQUENCE ID NO. 57); KPFVFLMIEQ (SEQUENCE ID NO. 58); NTKSPLFMGK (SEQUENCE ID NO. 59); and a combination thereof. 
     
     
         10 . The method of  claim 1 , wherein the composition is one or more peptide selected from the group consisting of AGAMFLEAIP (SEQUENCE ID NO. 56); MSIPPEVKFN (SEQUENCE ID NO. 57); KPFVFLMIEQ (SEQUENCE ID NO. 58); NTKSPLFMGK (SEQUENCE ID NO. 59); and a combination thereof. 
     
     
         11 . The method of  claim 1 , wherein the derivative of mammalian α1-antitrypsin comprises a peptoid compound selected from an oxadiazole, thiadiazole or triazole peptoid derivative of mammalian α1-antitrypsin or peptide thereof. 
     
     
         12 . A method for ameliorating macrophage infection in a subject by a  mycobacterium avium  complex (mac), comprising administering a therapeutically effective amount of a composition comprising mammalian α1-antitrypsin or derivative thereof to the subject exposed to  mycobacterium avium  complex (mac). 
     
     
         13 . A method for ameliorating the onset of a  Mycobacterium tuberculosis  or  Mycobacterium bovis  infection in a subject comprising, administering a therapeutically effective amount of a composition comprising mammalian α1-antitrypsin or derivative thereof to the subject. 
     
     
         14 . The method of  claim 13 , wherein the composition reduces or prevents onset of  Mycobacterium tuberculosis  or  Mycobacterium bovis  infection. 
     
     
         15 . The method of  claim 13 , wherein the composition comprises a composition of SEQ ID NO:61 or peptide derivative thereof. 
     
     
         16 . A method for ameliorating  Mycobacterium tuberculosis  or  Mycobacterium bovis  infection in a subject comprising, administering a therapeutically effective amount of a composition comprising one or more peptides selected from the group consisting of AGAMFLEAIP (SEQUENCE ID NO. 56); MSIPPEVKFN (SEQUENCE ID NO. 57); KPFVFLMIEQ (SEQUENCE ID NO. 58); NTKSPLFMGK (SEQUENCE ID NO. 59); and combinations thereof to the subject. 
     
     
         17 . The method of  claim 16 , further comprising administering at least one additional anti-bacterial agent to the subject. 
     
     
         18 . A method for treating a  Mycobacterium  infection of the lungs in a patient comprising: administering a therapeutically effective amount of a composition comprising mammalian α1-antitrypsin or derivative thereof to the patient. 
     
     
         19 . The method of  claim 18 , wherein the patient is administered an inhalable composition. 
     
     
         20 . A method for treating latent TB (LTBI) infection in a patient comprising: administering a therapeutically effective amount of a composition comprising mammalian α1-antitrypsin or derivative thereof to the patient.