Substituted polyamines as inhibitors of bacterial efflux pumps

Abstract

Disclosed are methods of treating bacterial infections including those caused by multidrug resistant bacteria using polyamine efflux pump inhibiting compounds, including for example N-benzylated polyazaalkanes, N-benzylated polyaminoalkanes, or mixed N-benzylated poly(aza/amino)alkanes, optionally in combination with other drugs such as antibiotics, as well as pharmaceutical compositions thereof.

1 . An inhibitor of an efflux pump for treating an infection caused by a microbe in a subject consisting of a polyazaalkane, polyaminoalkane, or mixed poly(aza/amino)alkane, any carbon atom of which may be hydroxyl, amino, or oxo substituted, and wherein said inhibitor contains at least two nitrogen atoms that are bonded to a lipophilic group, wherein said inhibitor inhibits efflux pump activity. 
     
     
         2 . The inhibitor of  claim 1 , wherein said inhibitor is an aminoglycoside comprising at least two nitrogen atoms that are each bonded to a lipophilic group. 
     
     
         3 . The inhibitor of  claim 1 , wherein said lipophilic group is a substituted or unsubstituted N-benzyl group. 
     
     
         4 . (canceled) 
     
     
         5 . The inhibitor of  claim 1 , wherein said inhibitor has the following structure: 
       
         
           
           
               
               
           
         
       
       wherein
 each Y is independently —(CX 2 ) m — (including a direct bond), —(CX 2 ) m O— (including —O—), —(CX 2 ) m NR—, —(CX 2 ) m H, (CX 2 ) m NHR, (CX 2 ) m OH, or two Y groups together form a ring structure, provided that a nitrogen/oxygen atom is not bonded to another nitrogen/oxygen atom, 
 each R is independently a —H or a lipophilic group, 
 each m is independently 0, 1, 2, 3; 4, 5, 6, 7, 8, 9, or 10, 
 each n is independently is 2, 3, 4, 5, 6, 7, 8, 9, or 10, and 
 each X is independently —H, —OH, or another Y group. 
 
     
     
         6 . The inhibitor of  claim 1 , wherein said inhibitor has the following structure: 
       
         
           
           
               
               
           
         
       
       wherein
 each Y is independently —(CX 2 ) m — (including a direct bond), —(CX 2 ) m O— (including —O—), —(CX 2 ) n ,NR—, —(CX 2 ) m H, (CX 2 ) m NHR, —(CX 2 ) m OH, or two Y groups together form a ring structure, provided that a nitrogen/oxygen atom is not bonded to another nitrogen/oxygen atom, 
 each R is independently a —H or a lipophilic group, 
 each m is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, 
 each n is independently is 2, 3, 4, 5, 6, 7, 8, 9, or 10, and 
 each X is independently —(CZ 2 ) p OH (including —OH), —(CZ 2 ) p H (including —H), —(CZ 2 ) p NH 2  (including —NH 2 ), —(CZ 2 ) p NHR, or two X groups together are —(CZ 2 ) p —NR—(CZ 2 ) p —, —(CZ 2 ) p —, —(CZ 2 ) p NR—, —O(CZ 2 ) p —, —(CZ 2 ) p —O—(CZ 2 ) p —, or a direct bond and both form a ring structure, 
 each p is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and 
 each Z is independently —H, —OH, —(CH 2 ) 2 H, —(CH 2 ) 2 H, —(CH 2 ) 2 H, —NH 2 , or —NHR. 
 
     
     
         7 . The inhibitor of  claim 1 , wherein said inhibitor has the following structure: 
       
         
           
           
               
               
           
         
         wherein 
         each Y is independently —(CX 2 ) m — (including a direct bond), —(CX 2 ) m O— (including —O—), —(CX 2 ) m H, —(CX 2 ) m NHR, —(CX 2 ) m OH, or two Y groups together form a ring structure, provided that a nitrogen/oxygen atom is not bonded to another nitrogen/oxygen atom, 
         each R is independently a —H or a lipophilic group, 
         each m is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, 
         each n is independently is 2, 3, 4, 5, 6, 7, 8, 9, or 10, and 
         each X is independently —H, —OH, or another Y group. 
       
     
     
         8 . The inhibitor of  claim 1 , wherein said inhibitor has the following structure: 
       
         
           
           
               
               
           
         
       
       wherein
 each Y is independently —(CX 2 ) m — (including a direct bond), —(CX 2 ) m O— (including —O—), —(CX 2 ) m NR—, —(CX 2 ) m H, —(CX 2 ) m NHR, —(CX 2 ) m OH, or two Y groups together form a ring structure, provided that a nitrogen/oxygen atom is not bonded to another nitrogen/oxygen atom, 
 each R is independently a —H or a lipophilic group, 
 each m is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, 
 each n is independently is 2, 3, 4, 5, 6, 7, 8, 9, or 10, and 
 each X is independently —(CZ 2 ) p OH (including —OH), —(CZ 2 ) p H (including —H), —(CZ 2 ) p NH 2  (including —NH 2 ), —(CZ 2 ) p NHR, or two X groups together are —(CZ 2 ) p —NR—(CZ 2 ) p —, —(CZ 2 ) p —, —(CZ 2 ) p NR—, —O(CZ 2 ) p —, —(CZ 2 ) p —O—(CZ 2 ) p —, or a direct bond and both form a ring structure, 
 each p is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and 
 each Z is independently —H, —OH, —(CH 2 ) 2 H, —(CH 2 ) 2 H, —(CH 2 ) 2 H, —NH 2 , or —NHR. 
 
     
     
         9 . The inhibitor of  claim 1 , wherein said inhibitor has the following structure: 
       
         
           
           
               
               
           
         
         wherein 
         each X is independently —(CZ 2 ) p OH (including —OH), —(CZ 2 ) p H (including —H), —(CZ 2 ) p NH 2  (including —NH 2 ), —(CZ 2 ) p NHR, or two X groups together are —(CZ 2 ) p —NR—(CZ 2 ) p —, —(CZ 2 ) p —, —(CZ 2 ) p NR—, —O(CZ 2 ) p —, —(CZ 2 ) p —O—(CZ 2 ) p —, or a direct bond and both form a ring structure, 
         each R is independently a —H or a lipophilic group, 
         each Z is independently —H, —OH, —(CH 2 ) 2 H, —(CH 2 ) 2 H, —(CH 2 ) 2 H, —NH 2 , or —NHR, 
         each m is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, 
         each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, 
         each p is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and 
         each q is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, 
         provided that p+n≧2. 
       
     
     
         10 . The inhibitor of  claim 1 , wherein said inhibitor has either of the following structures: 
       
         
           
           
               
               
           
         
       
       wherein
 each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, 
 m is 0, 1, 2, 3, 4, or 5 and 
 each R is independently a —H or a lipophilic group. 
 
     
     
         11 . A method for treating a microbial infection in an animal, comprising administering to an animal suffering from said infection an efflux pump inhibitor in an amount sufficient to reduce efflux pump activity, wherein said inhibitor is a polyazaalkane, polyaminoalkane, or mixed poly(azdamino)alkane, any carbon atom of which may be hydroxyl, amino, or oxo substituted, and wherein said inhibitor contains at least two nitrogen atoms that are bonded to a lipophilic group, such that infection is inhibited. 
     
     
         12 . (canceled) 
     
     
         13 . A method of enhancing the antimicrobial activity of an antimicrobial agent against a microbe, comprising contacting said microbe with said antimicrobial agent and an efflux pump inhibitor in an amount effective to inhibit an efflux pump in said microbe, wherein said inhibitor is a polyazaalkane, polyaminoalkane, or mixed poly(aza/amino)alkane, any carbon atom of which may be hydroxyl, amino, or oxo substituted, and wherein said inhibitor contains at least two nitrogen atoms that are bonded to a lipophilic group, such that said activity is enhanced. 
     
     
         14 .- 16 . (canceled) 
     
     
         17 . The method of  claim 11 , wherein said microbe is a drug resistant microbe. 
     
     
         18 .- 23 . (canceled) 
     
     
         24 . The method of  claim 11 , further comprising administering an antibiotic to the subject. 
     
     
         25 .- 28 . (canceled) 
     
     
         29 . A pharmaceutical composition, comprising an efflux pump inhibitor of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         30 .- 37 . (canceled)