Compounds for inhibiting bacterial growth via phosphatidylglycerol binding

Abstract

Antibacterial small molecule compounds, termed liptins, bind to phosphatidylglycerol in bacterial plasma membranes. The small molecule compounds comprise a three-dimensional complementary binding pocket for phosphatidylglycerol, disrupting membrane function in a bacteriostatic or bactericidal manner. Methods of inhibiting bacterial growth and/or treating Gram-positive or Gram-negative bacterial infection using such compounds are also disclosed.

1 . An antibacterial small molecule compound that binds to phosphatidylglycerol in bacterial plasma membranes, said small molecule comprising a central scaffold and a plurality of functional groups cooperatively forming a three-dimensional complementary binding pocket for said phosphatidylglycerol, wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       combinations thereof, and substituted forms thereof, where:
 M is 3, 4, or 5; 
 N is 1, 2, 3, or 4; 
 each R b  is —CH 2 CH 2 OH, —CH(OH)CH 2 OH, or —CH 2 CO 2 NHOH; 
 each R c  is —CONHPh, (2H) + +X − , or —C(═NH + )NHR′, where R′ is an alkyl (e.g., C 1 -C 8  alkyl) or aryl group; 
 each R d  is an —COHNalkyl (preferably C3-C8 alkyl), —CONHCH 2 CH 2 OCH 2 C 6 H 5 , —CONHCH 2 CH 2 OH, —CONH(CH 2 CH 2 O) 3 CH 2 CH 3 , —CONHCH 2 CH 2 CH 3 , —CH 2 NH 3   + X − , —CH 2 NH 2   + CH 2 C 6 H 5 , —CH 2 NH 2   + CH 2 CH 2 CH 3 , —CH 2 NH 2   + CH 2 (CH 2 ) 4 CH 3 , —CH 2 CH 2 (OCH 2 CH 2 )yCH 3 , —CH 2 Ph, or —CH 2 R″, where R″ is 2-(aminomethyl)-5-methylphenol or 5-(aminomethyl)-2-methylphenol; and 
 X— is any anionic counter ion. 
 
     
     
         2 . The compound of  claim 1 , wherein said compound is bacteriostatic. 
     
     
         3 . The compound of  claim 1 , wherein said compound is bactericidal. 
     
     
         4 . An antibacterial composition comprising a bacteriostatic or bactericidal amount of an antibacterial small molecule compound according to  claim 1  dispersed in a pharmaceutically-acceptable carrier. 
     
     
         5 . The composition of  claim 4 , wherein said carrier is selected from the group consisting of saline, buffered saline, sterile water, aqueous dextrose solutions, aqueous glycerol solutions, ethanol, allantoic fluid, oil-in-water emulsion, water-in-oil emulsions, dimethyl sulfoxide, petroleum jelly, cocoa butter, cottonseed oil, olive oil, sodium pyruvate, vitamin E, white petrolatum, white wax, stearyl alcohol, cholesterol, mineral oil, ceryl ester wax, sodium lauryl sulfate, propylene glycol, polyethylene glycol, and mixtures thereof. 
     
     
         6 . The composition of  claim 4 , said composition being substantially free of antibiotics and/or antimicrobial peptides. 
     
     
         7 . The composition of  claim 4 , said composition consisting essentially of said small molecule compound and said carrier. 
     
     
         8 . The composition of  claim 4 , said compound has a minimum inhibitory concentration (MIC) of from about 1 to about 4 μM. 
     
     
         9 . A method of inhibiting bacterial growth, said method comprising contacting bacteria with an antibacterial small molecule compound that binds to phosphatidylglycerol in bacterial plasma membranes, said small molecule comprising a central scaffold and a plurality of functional groups, at least one functional group for binding to an anion, and at least one functional group for glycerol binding, said scaffold and said functional groups cooperatively forming a three-dimensional complementary binding pocket for said phosphatidylglycerol. 
     
     
         10 . The method of  claim 9 , wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       combinations thereof, and substituted forms thereof, where:
 X −  is any anionic counter ion; 
 m is 3, 4, or 5; 
 n is 3, 4, 5, or 6; 
 M is 3, 4, or 5; 
 N is 1, 2, 3, or 4; 
 each R a  is —(CH 2 ) 2 CONHC 6 H 13 , —CH 2 CONHC 6 H 13 , —(CH 2 ) 2 CONH(CH 2 ) y NHCOCH 3 , —(CH 2 ) 2 CONH(CH 2 ) y NHCONH(CH 2 ) y CH 3 , —(CH 2 ) 2 CONHOH, or —NHNHCONH(CH 2 ) y CH 3 , where each y is 1, 2, 3, or 4; 
 each R b  is —CH 2 CH 2 OH, —CH(OH)CH 2 OH, or —CH 2 CO 2 NHOH; 
 each R c  is —CONHPh, (2H) + +X − , or —C(═NH + )NHR′, where R′ is an alkyl (e.g., C 1 -C 8  alkyl) or aryl group; and 
 each R d  is an —COHNalkyl (preferably C3-C8 alkyl), —CONHCH 2 CH 2 OCH 2 C 6 H 5 , —CONHCH 2 CH 2 OH, —CONH(CH 2 CH 2 O) 3 CH 2 CH 3 , —CONHCH 2 CH 2 CH 3 , —CH 2 NH 3   + X − , —CH 2 NH 2   + CH 2 C 6 H 5 , —CH 2 NH 2   + CH 2 CH 2 CH 3 , —CH 2 NH 2   + CH 2 (CH 2 ) 4 CH 3 , —CH 2 CH 2 (OCH 2 CH 2 ) y CH 3 , —CH 2 Ph, or —CH 2 R″, where R″ is 2-(aminomethyl)-5-methylphenol or 5-(aminomethyl)-2-methylphenol. 
 
     
     
         11 . The method of  claim 9 , wherein said antibacterial small molecule compound is dispersed in a carrier for administration or application. 
     
     
         12 . The method of  claim 9 , wherein said compound is fluorescent, said method further comprising monitoring changes in fluorescence of said compound after said contacting. 
     
     
         13 . A method of treating bacterial infection in a subject suffering from an infected area, said method contacting said infected area with therapeutically-effective amount of an antibacterial small molecule compound that binds to phosphatidylglycerol in bacterial plasma membranes, said small molecule comprising a central scaffold and a plurality of functional groups, at least one functional group for binding to an anion, and at least one functional group for glycerol binding, said scaffold and said functional groups cooperatively forming a three-dimensional complementary binding pocket for said phosphatidylglycerol. 
     
     
         14 . The method of  claim 13 , wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       combinations thereof, and substituted forms thereof, where:
 X −  is any anionic counter ion; 
 m is 3, 4, or 5; 
 n is 3, 4, 5, or 6; 
 M is 3, 4, or 5; 
 N is 1, 2, 3, or 4; 
 each R a  is —(CH 2 ) 2 CONHC 6 Ho, —CH 2 CONHC 6 H 13 , —(CH 2 ) 2 CONH(CH 2 ) y NHCOCH 3 , —(CH 2 ) 2 CONH(CH 2 ) y NHCONH(CH 2 ) y CH 3 , —(CH 2 ) 2 CONHOH, or —NHNHCONH(CH 2 ) y CH 3 , where each y is 1, 2, 3, or 4; 
 each R b  is —CH 2 CH 2 OH, —CH(OH)CH 2 OH, or —CH 2 CO 2 NHOH; 
 each R c  is —CONHPh, (2H) + +X − , or —C(═NH + )NHR′, where R′ is an alkyl (e.g., C 1 -C 8  alkyl) or aryl group; and 
 each R d  is an —COHNalkyl (preferably C3-C8 alkyl), —CONHCH 2 CH 2 OCH 2 C 6 H 5 , —CONHCH 2 CH 2 OH, —CONH(CH 2 CH 2 O) 3 CH 2 CH 3 , —CONHCH 2 CH 2 CH 3 , —CH 2 NH 3   + X − , —CH 2 NH 2   + CH 2 C 6 H 5 , —CH 2 NH 2   + CH 2 CH 2 CH 3 , —CH 2 NH 2   + CH 2 (CH 2 ) 4 CH 3 , —CH 2 CH 2 (OCH 2 CH 2 )yCH 3 , —CH 2 Ph, or —CH 2 R″, where R″ is 2-(aminomethyl)-5-methylphenol or 5-(aminomethyl)-2-methylphenol. 
 
     
     
         15 . The method of  claim 13 , wherein said contacting comprises directly applying said antibacterial small molecule compound to said infected area of said subject. 
     
     
         16 . The method of  claim 13 , wherein said contacting comprises systemically administering said antibacterial small molecule compound to said subject. 
     
     
         17 . The method of  claim 13 , wherein said bacterial infection is caused by Gram-negative or Gram-positive bacteria. 
     
     
         18 . The method of  claim 17 , wherein said bacteria is selected from the group consisting of  Acinetobacter baumannii, Escherichia coli, Staphylococcus aureus, Mycobacterium smegmatis, Enterococcus faecalis, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus mitis, Streptococcus mutans, Streptococcus bovis, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterococcus faecium, Staphylococcus epidermidis, Staphylococcus haemolyticus, Salmonella typhimurium, Bacillus subtilis, Neisseria meningitides, Neisseria gonorrhoeae , and  Haemophilus influenza.