Nucleic Acid Complexes

Abstract

The present invention relates to complexes of transcription factor decoys, their delivery to bacteria and their formulation. In particular, the present invention resides in an antibacterial complex comprising a nucleic acid sequence and one or more delivery moieties selected from quaternary amine compounds; bis-aminoalkanes and unsaturated derivatives thereof, wherein the amino component of the aminoalkane is an amino group forming part of a heterocyclic ring; and an antibacterial peptide.

1 - 10 . (canceled) 
     
     
         11 . A pharmaceutical composition comprising:
 i) a complex comprising a nucleic acid sequence comprising the sequence of a native cellular binding site for a bacterial transcription factor;   ii) at least one delivery moiety, wherein the delivery moiety is selected from quaternary amine compounds; bis-aminoalkanes and unsaturated derivatives thereof, wherein the amino component of the aminoalkane is an amino group forming part of a heterocyclic ring; and   iii) at least one physiologically acceptable carrier or excipient;   wherein the complex and the at least one delivery moiety together are an active ingredient.   
     
     
         12 . The pharmaceutical composition according to  claim 11 , wherein the delivery moiety is selected from a quaternary derivative of quinoline or acridine. 
     
     
         13 . The pharmaceutical composition according to  claim 11 , wherein the delivery moiety is a bis-quinolinium. 
     
     
         14 . The pharmaceutical composition according to  claim 11 , wherein the delivery moiety is an analogue of dequalinium. 
     
     
         15 . The pharmaceutical composition according to  claim 14 , wherein the alkyl chain of the dequalinium analogue has between 8 and 14 methylene groups. 
     
     
         16 . The pharmaceutical composition according to  claim 14 , wherein the alkyl chain has 10 or 12 methylene groups. 
     
     
         17 . The pharmaceutical composition according to  claim 11 , wherein the quaternary amine compound is 10,10′-(decane-1,10-diyl)bis(9-amino-1,2,3,4-tetrahydroacridinium) dichloride. 
     
     
         18 . The pharmaceutical composition according to  claim 11 , wherein the quaternary amine compound is 10,10′-(dodecane-1,12-diyl)bis(9-amino-1,2,3,4-tetrahydroacridinium) dichloride. 
     
     
         19 . The pharmaceutical composition according to  claim 11 , wherein the quaternary amine compounds and bis-aminoalkanes and unsaturated derivatives thereof are selected from compounds of the formula (I):
   Q−(CH 2 ) p −A—(CH 2 ) q −R 3    (I)
   
       wherein Q is selected from:
 (a) a group Q 1  having the formula: 
 
       
         
           
           
               
               
           
         
       
       and
 (b) a group Q 2 , Q 2 —NH—, or Q 2 —S— wherein Q 2  is selected from monocyclic, bicyclic and tricyclic heteroaromatic groups of 5 to 14 ring members, of which 1, 2 or 3 are heteroatom ring members selected from N, O and S provided that at least one nitrogen ring member is present, wherein the heteroaromatic groups are optionally substituted by one or two substituents R 4a  and wherein the said one nitrogen ring member may form an N-oxide or may be substituted with C 1-4  alkyl, phenyl-C 1-4  alkyl or di-phenyl-C 1-4  alkyl to form a quaternary group, wherein the phenyl moieties in each case are optionally substituted with one or two halogen, methyl or methoxy groups; 
 m is 0 or 1; 
 n is 0 or 1; 
 p and q are the same or different and each is an integer from 1 to 12; 
 A is a bond or is selected from a naphthalene, biphenyl, terphenyl, phenanthrene, fluorene, stilbene, a group C 6 H 4 (CH 2 ) r C 6 H 4 , a group C 6 H 4 —C≡C—C 6 H 4 , a pyridine-2,6-diyl-bis(benzene-1,4-diyl) group, a group CH═CH—(CH 2 ) s —(CH═CH) t -; and a group C≡C—(CH 2 ) u —(C≡C) v -; wherein r is 0-4, s is 0 to 4, t is 0 or 1; u is 0-4 and v is 0 or 1; 
 when n is 1, R 0 , R 1  and R 2  are each selected from C 1-4  alkyl; and when n is 0, then N, R 1  and R 2  together form a monocyclic, bicyclic or tricyclic heteroaromatic group of 5 to 14 ring members, of which one is the nitrogen atom N and 0, 1 or 2 are further heteroatom ring members selected from N, O and S, and wherein the heteroaromatic group is optionally substituted by one or two substituents R 4b ; and 
 R 3  is selected from hydrogen, C 1-4  alkyl, halogen, monocyclic carbocyclic groups of 3 to 7 ring members each optionally substituted by one or two substituents R 4c , a group Q; a group—NH-Q 2 , a group —O-Q 2  and a group —S-Q 2 ; and 
 R 4a , R 4b  and R 4c  are the same or different and each is selected from C 1-4  alkyl optionally substituted with one or more fluorine atoms: C 1-4  alkoxy optionally substituted with one or more fluorine atoms; nitro; amino; mono- and di-C 1-4  alkylamino; halogen; phenyl-C 1-2  alkyl wherein the phenyl moiety is optionally substituted with one or two methoxy, methyl or halogen substituents; ureido and guanidinyl. 
 
     
     
         20 . The pharmaceutical composition according to  claim 19 , wherein the compound of formula (I) is represented by formula (II): 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , m, p, A, q and R 3  are as defined in  claim 19 . 
       
     
     
         21 . The pharmaceutical composition according to  claim 20 , wherein R 3  is Q 1  and n in each instance is 0, and wherein the compound of formula (II) is represented by formula (III): 
       
         
           
           
               
               
           
         
       
     
     
         22 . The pharmaceutical composition according to  claim 19 , wherein the compound of formula (I) is represented by formula (IV): 
       
         
           
           
               
               
           
         
         wherein: 
         p and q are the same or different and each is an integer from 1 to 12; 
         A is a bond or is selected from naphthalene, biphenyl, terphenyl, phenanthrene, fluorene, stilbene, a group C 6 H 4 (CH 2 ) r C 6 H 4 , a group C 6 H 4 —C≡C—C 6 H 4 , a pyridine-2,6-diyl-bis(benzene-1,4-diyl) group, a group CH═CH—(CH 2 ) s —(CH═CH) t -; and a group C≡C—(CH 2 ) u —(C≡C) v -; wherein r is 0-4, s is 0 to 4, t is 0 or 1; u is 0-4 and v is 0 or 1; 
         R 8 , R 9  and R 10  are the same or different and are each selected from hydrogen; C 1-4  alkyl optionally substituted with one or more fluorine atoms: C 1-4  alkoxy optionally substituted with one or more fluorine atoms; nitro; amino; mono- and di-C 1-4  alkylamino; halogen, phenyl-C 1-2  alkyl wherein the phenyl moiety is optionally substituted with one or two methoxy, methyl or halogen substituents; ureido and guanidinyl; or R 9  and R 10  link together to form an alkylene chain (CH 2 ) w  wherein w is 3 to 5; and R 8a , R 9a  and R 10a  are the same or different and are each selected from hydrogen; C 1-4  alkyl optionally substituted with one or more fluorine atoms: C 1-4  alkoxy optionally substituted with one or more fluorine atoms; nitro; amino; mono- and di-C 1-4  alkylamino; halogen, phenyl-C 1-2  alkyl wherein the phenyl moiety is optionally substituted with one or two methoxy, methyl or halogen substituents; ureido and guanidinyl; or R 9a  and R 10a  link together to form an alkylene chain (CH 2 ) w  wherein w is 3 to 5. 
       
     
     
         23 . The pharmaceutical composition according to  claim 22 , wherein the compound of formula (IV) is represented by formula (V): 
       
         
           
           
               
               
           
         
         wherein: 
         r is an integer from 2 to 24; 
         R 8 , R 9  and R 10  are the same or different and are each selected from hydrogen; C 1-4  alkyl optionally substituted with one or more fluorine atoms: C 1-4  alkoxy optionally substituted with one or more fluorine atoms; nitro; amino; mono- and di-C 1-4  alkylamino; halogen, phenyl-C 1-2  alkyl wherein the phenyl moiety is optionally substituted with one or two methoxy, methyl or halogen substituents; ureido and guanidinyl; or R 9  and R 10  link together to form an alkylene chain (CH 2 ) w  wherein w is 3 to 5; and R 8a , R 9a  and R 10a  are the same or different and are each selected from hydrogen; C 1-4  alkyl optionally substituted with one or more fluorine atoms: C 1-4  alkoxy optionally substituted with one or more fluorine atoms; nitro; amino; mono- and di-C 1-4  alkylamino; halogen, phenyl-C 1-2  alkyl wherein the phenyl moiety is optionally substituted with one or two methoxy, methyl or halogen substituents; ureido and guanidinyl; or R 9a  and R 10a  link together to form an alkylene chain (CH 2 ) w  wherein w is 3 to 5; 
         wherein: 
         (i) when R 10  and R 10a  are both hydrogen or are both methyl, and R 9  and R 9a  are both hydrogen, then at least one of R 8  and R 8a  is other than hydrogen, amino or dimethylamino; and 
         (ii) when R 9  and R 10  link together to form an alkylene chain (CH 2 ) w  wherein w is 4 and R 9a  and R 10a  link together to form an alkylene chain (CH 2 ) w  wherein w is 4, then at least one of R 8  and R 8a  is other than amino. 
       
     
     
         24 . The pharmaceutical composition according to  claim 11 , wherein the native cellular binding site comprises the sequence of a bacterial Sig binding site. 
     
     
         25 . The pharmaceutical composition according to  claim 24 , wherein the nucleic acid sequence of the bacterial Sig binding site has the sequence set out in SEQ ID NOs: 9, 10, 30, 31, 39, 40 or 41. 
     
     
         26 . The pharmaceutical composition according to  claim 11 , wherein the native cellular binding site comprises the sequence of a bacterial Fur binding site. 
     
     
         27 . The pharmaceutical composition according to  claim 26 , wherein the nucleic acid sequence has the sequence set out in SEQ ID NOs: 11, 12 or 13. 
     
     
         28 . The pharmaceutical composition according to  claim 11 , wherein the composition is formulated for administration separately or simultaneously in combination with one or more antibiotics. 
     
     
         29 . The pharmaceutical composition according to  claim 11 , wherein the composition is formulated for oral administration. 
     
     
         30 . The pharmaceutical composition according to  claim 11 , wherein the composition is formulated for delivery of the active ingredient to the gut. 
     
     
         31 . A method of treating a bacterial infection in a subject, the method comprising administering the pharmaceutical composition of  claim 11  to treat the bacterial infection in the subject.