INHIBITORS OF METALLO-ß-LACTAMASE-ENZYMES

Abstract

The present application relates to combination treatments for bacterial infections. For example, the application relates to the use of one or more β-lactam antibiotics and one or more compounds of Formula I: (I) for treatment of a metallo-β-lactamase-expressing bacterial infection or a disease, disorder or condition arising from a metallo-β-lactamase-expressing bacterial infection.

1 . A pharmaceutical composition comprising:
 one or more carbapenem antibiotic; and   a compound being an aspergillomarasmine B (AM-B) compound represented by:   
       
         
           
           
               
               
           
         
         or a lycomarasmine compound represented by: 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt and/or solvate thereof; 
         the one or more carbapenem antibiotic and the AM-B compound, lycomarasmine compound, or pharmaceutically acceptable salt and/or solvate thereof, are present in amounts that are effective to treat a bacterial infection, or a disease, disorder or condition arising from a bacterial infection, 
         wherein the bacterial infection is an infection of at least one metallo-β-lactamase-expressing bacterium. 
       
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the compound is the AM-B compound or pharmaceutically acceptable salt and/or solvate thereof. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the compound is the lycomarasmine compound or pharmaceutically acceptable salt and/or solvate thereof. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the AM-B compound, lycomarasmine compound, or pharmaceutically acceptable salt and/or solvate thereof, is a natural product extracted from a fungus. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the AM-B compound, lycomarasmine compound, or pharmaceutically acceptable salt and/or solvate thereof, is prepared by chemical synthesis. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the one or more antibiotic and the AM-B compound, lycomarasmine compound, or pharmaceutically acceptable salt and/or solvate thereof, are formulated in a single dosage form. 
     
     
         7 . A pharmaceutical composition comprising:
 one or more β-lactam antibiotic; and   a compound being an aspergillomarasmine B (AM-B) represented by:   
       
         
           
           
               
               
           
         
         or a lycomarasmine compound represented by: 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt and/or solvate thereof; and 
         the one or more β-lactam antibiotic and the AM-B compound, lycomarasmine compound, or pharmaceutically acceptable salt and/or solvate thereof, are present in amounts that are effective for improving the efficacy of the one or more β-lactam antibiotic for the treatment of a bacterial infection or a disease, disorder or condition arising from a bacterial infection, 
         wherein the one or more β-lactam antibiotic and the AM-B compound, lycomarasmine compound, or pharmaceutically acceptable salt and/or solvate thereof, are formulated in separate dosage forms, or the one or more β-lactam antibiotic and the AM-B compound, lycomarasmine compound, or pharmaceutically acceptable salt and/or solvate thereof, are formulated in a single dosage form, 
         wherein the bacterial infection is an infection of at least one metallo-β-lactamase-expressing bacterium. 
       
     
     
         8 . The pharmaceutical composition of  claim 7 , wherein the compound is the AM-B compound or pharmaceutically acceptable salt and/or solvate thereof. 
     
     
         9 . The pharmaceutical composition of  claim 7 , wherein the compound is the lycomarasmine compound or pharmaceutically acceptable salt and/or solvate thereof. 
     
     
         10 . The pharmaceutical composition of  claim 7 , wherein the AM-B compound, lycomarasmine compound, or pharmaceutically acceptable salt and/or solvate thereof, is a natural product extracted from a fungus. 
     
     
         11 . The pharmaceutical composition of  claim 7 , wherein the AM-B compound, lycomarasmine compound, or pharmaceutically acceptable salt and/or solvate thereof, is prepared by chemical synthesis. 
     
     
         12 . The pharmaceutical composition of  claim 7 , wherein the β-lactam antibiotic and the AM-B compound, lycomarasmine compound, or pharmaceutically acceptable salt and/or solvate thereof, are formulated in a single dosage form. 
     
     
         13 . The pharmaceutical composition of  claim 7 , wherein the one or more β-lactam antibiotic is selected from penicillin derivatives, cephalosporins, monobactams and carbapenems. 
     
     
         14 . A method of improving the efficacy of a β-lactam antibiotic for treating a bacterial infection in a subject in need thereof comprising administering to the subject who suffers from the bacterial infection an effective amount of the composition according to  claim 7 ,
 wherein the bacterial infection is an infection of at least one metallo-β-lactamase-expressing bacterium. 
 
     
     
         15 . A method of treating a bacterial infection in a subject in need thereof comprising administering to the subject who suffers from the bacterial infection an effective amount of one or more β-lactam antibiotic in combination with an effective amount of a compound being an aspergillomarasmine B (AM-B) compound represented by: 
       
         
           
           
               
               
           
         
         or a lycomarasmine compound represented by: 
       
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt and/or solvate thereof,
 wherein the bacterial infection is an infection of at least one metallo-β-lactamase-expressing bacterium. 
 
     
     
         16 . The method of  claim 15 , wherein the metallo-β-lactamase-expressing bacterium is at least one carbapenem-resistant Gram-negative bacteria. 
     
     
         17 . The method of  claim 15 , wherein the metallo-β-lactamase-expressing bacterium is at least one bacterium belonging to the family Enterobacteriaceae,  Acinetobacter  or  Pseudomonas.    
     
     
         18 . The method of  claim 15 , wherein the one or more β-lactam antibiotic is selected from penicillin derivatives, cephalosporins, monobactams and carbapenems. 
     
     
         19 . The method of  claim 15 , wherein the compound is the AM-B compound or pharmaceutically acceptable salt and/or solvate thereof. 
     
     
         20 . The method of  claim 15 , wherein the compound is the lycomarasmine compound or pharmaceutically acceptable salt and/or solvate thereof.