Microbiological Process

Abstract

A process for the microbial synthesis of migalastat, specifically a process for the production of migalastat comprising culturing a microorganism under conditions such that at least one imino sugar is produced and detecting and/or isolating an imino sugar produced by said microorganism, and the microorganisms used in this process. The invention also comprises migalastat produced according to the above method and pharmaceutical compositions and uses thereof.

1 . A process for the production of migalastat, said process comprising the steps of: (a) culturing a microorganism under conditions such that at least one imino sugar is produced, and (b) detecting and/or isolating an imino sugar produced by said microorganism. 
     
     
         2 . A process for the production of migalastat, said process comprising the steps of:
 a. culturing a microorganism under conditions whereby at least one imino sugar is produced,   b. detecting and/or recovering an imino sugar produced by said microorganism, and   c. if said detected and/or recovered imino sugar is not migalastat, converting said detected and/or isolated imino sugar to migalastat.   
     
     
         3 . The process as claimed in  claim 1 , wherein said microorganism comprises a bacterium. 
     
     
         4 . The process as claimed in  claim 3 , wherein said bacterium is selected from the group consisting of:  Streptomyces, Bacillus; Paenibacillus, Cornyebacterium; Lactobacillus; Lactococci; Salmonella; Escherichia; Klebsiella; Serratia ; and  Proteus.    
     
     
         5 . The process as claimed in  claim 4 , wherein said bacterium comprises  Streptomyces  bacteria selected from the group consisting of:  Streptomyces lydicus; Streptomyces subrutilus; Streptomyces lavendulae; Streptomyces anulatus; Streptomyces  sp BTA530 (NCIMB 42142); and  Streptomyces lydicus  ATCC319075. 
     
     
         6 . The process as claimed in  claim 1 , wherein said culturing is carried out by a fermentation process selected from the group consisting of: batch fermentation; fed-batch fermentation; and continuous fermentation. 
     
     
         7 . The process as claimed in  claim 6 , wherein the fermentation process comprises a seed fermentation and a final fermentation. 
     
     
         8 . The process as claimed in  claim 1 , wherein said detecting step (b) is carried out using an α-galactosidase A activity assay. 
     
     
         9 . The process as claimed in  claim 2 , wherein said recovering step (c) comprises at least one process selected from the group consisting of: desludging; filtration; fractionation; pH adjustment; concentration; conversion to a salt; and recrystallization. 
     
     
         10 . The process as claimed in  claim 3 , wherein said conditions are suitable for said bacteria to produce migalastat, and wherein the process comprises detecting migalastat in the culture, and recovering migalastat from the culture. 
     
     
         11 . The process as claimed in  claim 3 , wherein said bacteria are cultured in a medium comprising lactose. 
     
     
         12 . The process as claimed in  claim 3 , wherein said conditions are suitable for said bacteria to produce galactostatin, and wherein the process comprises detecting galactostatin in the culture and converting said galactostatin to migalastat. 
     
     
         13 . The process as claimed in  claim 12 , wherein said galactostatin is converted to migalastat in culture. 
     
     
         14 . The process as claimed in  claim 12 , wherein said galactostatin is isolated before being converted to migalastat. 
     
     
         15 . The process as claimed in  claim 12 , wherein the converting step is carried out by a process selected from the group consisting of: chemical conversion and biotransformation. 
     
     
         16 . The process as claimed in  claim 1 , comprising the further step (d) of converting migalastat to migalastat hydrochloride. 
     
     
         17 . Migalastat produced according to the process of  claim 1  or migalastat hydrochloride produced according to the process of  claim 16 . 
     
     
         18 . A pharmaceutical composition comprising migalastat produced according to the process of  claim 1 . 
     
     
         19 . A method of treating Fabry disease in a patient in need thereof by administering an effective amount of the pharmaceutical composition as claimed in  claim 18 . 
     
     
         20 . Isolated  Streptomyces  bacteria selected from the group consisting of:  Streptomyces  sp BTA530 (NCIMB 42142) and  Streptomyces  sp mutant BTM4 (NCIMB 42358).