Methods for the Treatment of an Infectious Bacterial Disease with an Anti-Lactone or Lactone Derived Signal Molecules Antibody

Abstract

The present invention relates to methods for the control of virulence of infectious bacteria by modulating the extra-cellular concentration of bacterial cell signalling molecules. Derivatives of cell signalling molecules are conjugated to suitable carrier proteins and used to isolate high affinity receptors recognising the native signal molecule(s). By binding to signalling molecules, the receptors reduce and maintain extra-cellular concentrations of signal molecules below the threshold level that would otherwise result in certain opportunistic pathogens adopting a virulent form, and can transform virulent organisms to non-virulent states. These receptors have applications for the treatment of individuals with susceptibility to infection, the treatment of patients with existing infections, in disease monitoring and management, and in related applications where the host for infection is an animal or plant.

1 . An antibody to a lactone or a lactone-derived signal molecule secreted by bacteria. 
     
     
         2 . An antibody as claimed in  claim 1 , in which the lactone signal molecule is a homoserine molecule or a peptide thiolactone molecule. 
     
     
         3 . An antibody as claimed in  claim 2 , in which the homoserine lactone molecule has a general formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       where n=0 to 12. 
     
     
         4 . An antibody as claimed in  claim 3 , in which the homoserine lactone molecule of general formula I is N-butanoly-L-homoserine lactone (BHL) where n=0, N-dodecanoyl-L-homoserine lactone (dDHL) where n=8 and n-tetradecanoyl-L-homoserine lactone (tDHL) where n=10. 
     
     
         5 . An antibody as claimed in  claim 3 , in which the homoserine lactone molecule of general formula II is N-(−3-oxohexanoyl)-L-homoserine lactone (OHHL) where n=2 and N-(−3-oxododecanoyl)-L-homoserine lactone (OdDHL) where n=8. 
     
     
         6 . An antibody as claimed in  claim 3 , in which the homoserine lactone molecule of general formula III is N-(−3-hydroxybutanoyl)-L-homoserine lactone (HBHL) where n=0. 
     
     
         7 . An antibody as claimed in  claim 2  in which the peptide thiolactone has a general formula (IV) as follows: 
       
         
           
           
               
               
           
         
       
       where X is any amino acid and n=1 to 10. 
     
     
         8 . An antibody as claimed in  claim 7 , in which the peptide thiolactone molecule is: 
       
         
           
           
               
               
           
         
       
     
     
         9 . An antibody as claimed in  claim 1 , in which the lactone-derived signal molecule is a furanosyl borate diester. 
     
     
         10 . An antibody as claimed in  claim 9 , in which the furanosyl borate diester is Auto Inducer-2 (AI-2), 
       
         
           
           
               
               
           
         
       
     
     
         11 . An antibody as claimed in  claim 1 , in which the lactone-derived signal molecule is Pro-AI-2 or a C 1 -C 10  saturated or unsaturated carboxylic acid derivative thereof 
       
         
           
           
               
               
           
         
       
     
     
         12 . An antibody as claimed in  claim 1  which is a polyclonal antibody 
     
     
         13 . An antibody as claimed in  claim 1  which is a monoclonal antibody. 
     
     
         14 . An antibody as claimed in  claim 1  which is a single chain antibody (scAb) 
     
     
         15 . An antibody as claimed in  claim 1  which is an antibody fragment. 
     
     
         16 . An antibody as claimed in  claim 15 , in which the antibody fragment is a single chain variable fragment (scFv). 
     
     
         17 . An antibody as claimed in  claim 15 , in which the antibody fragment is a single domain fragment. 
     
     
         18 . A pharmaceutical composition comprising an antibody as defined in  claim 1 . 
     
     
         19 . A method for the treatment of bacterial infection of a subject, the method comprising administration of an antibody as defined in  claim 1 . 
     
     
         20 . A kit of parts comprising an antibody as defined in  claim 1 . provided in unit dosage form. 
     
     
         21 . An antibody as defined in  claim 1  for use in medicine. 
     
     
         22 . The use of an antibody as defined in  claim 1  for use in the preparation of a medicament for the treatment of bacterial infection. 
     
     
         23 . A method of screening a population of specific binding molecules for an anti-bacterial specific binding molecule, the method comprising conjugating a bacterial lactone or lactone-derived signal molecule to a carrier molecule and using the conjugate so formed to identify a specific binding molecule that specifically binds to the conjugate from the population of specific binding molecules. 
     
     
         24 . A method as claimed in  claim 23 , in which the specific binding molecule is an antibody or a fragment thereof. 
     
     
         25 . A method as claimed in  claim 24 , in which the antibody is a monoclonal antibody. 
     
     
         26 . A method as claimed in  claim 24 , in which the antibody is a polyclonal antibody. 
     
     
         27 . A method as claimed in  claim 23 , in which the carrier molecule is a protein. 
     
     
         28 . A method as claimed in  claim 23 , in which the bacterial lactone signal molecule is a homoserine molecule or a peptide thiolactone molecule. 
     
     
         29 . A method as claimed in  claim 23 , in which the lactone derived signal molecule is a furanosyl borate diester, such as AI-2, or Pro-AI-2 or a C 1 -C 10  saturated or unsaturated carboxylic acid derivative thereof. 
     
     
         30 . A method as claimed in  claim 23 , in which the population of specific binding molecules is a phage display library. 
     
     
         31 . A specific binding molecule identified by a the method of  claim 23  for use in medicine. 
     
     
         32 . The use of a specific binding molecule identified by a method according to  claim 23  in the preparation of a medicament for the treatment of a bacterial infection. 
     
     
         33 . The use of a bacterial lactone or lactone-derived signal molecule to screen a population of specific binding molecules in order to identify a specific binding molecule that specifically binds to said bacterial lactone signal molecule. 
     
     
         34 . A method of treatment of a bacterial infection of a subject, the method comprising isolation of a bacterial lactone or lactone-derived signal molecule in a sample from said subject and using said bacterial lactone signal molecule to screen a population of specific binding molecules for an anti-bacterial specific binding molecule to identify a specific binding molecule that specifically binds to the signal molecule, and administering said specific binding molecule so identified to a patient in need thereof. 
     
     
         35 . A method as claimed in  claim 34 , in which the sample is of blood, saliva, tissue, cerebro-spinal fluid, tears, semen, urine, faeces, pus, skin, or mucous secretions.