Natural product antibiotics and analogs thereof

Abstract

Provided herein are pure and isolated natural products and analogs thereof of Formula (I), (II), (III), and (IV), pharmaceutical compositions thereof, and methods of use, for example, for treating a bacterial infection. Further provided are methods useful in identifying an inhibitor of bacterial sugar fermentation in a bacterial strain, such as a compound (inhibitor) of Formula (I), (II), (III), or (IV): or a pharmaceutically acceptable salt thereof.

1 - 5 . (canceled) 
     
     
         6 . A method of treating a bacterial infection in a subject comprising administering an effective amount of a compound of Formula (II): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, to the subject; 
       wherein:
 each occurrence of R 1 , R 2 , R 4a , R 4b , R 5a , and R 5b , is independently hydrogen or halogen; 
 R B  is hydrogen, substituted or unsubstituted C 1-3  alkyl, —C(═O)R B2 , —C(═O)OR B1 , —C(═O)SR B1 , —C(═O)N(R B1 ) 2 , —S(═O) 2 R B2 , —S(═O) 2 OR B1 , —P(═O) 2 R B2 , —P(═O) 2 OR B1 , —P(═O)(OR B1 ) 2 , —P(═O)(R B2 ) 2 , or —P(═O)(R B2 )(OR B1 ); 
 R C  is hydrogen, substituted or unsubstituted C 1-3  alkyl, —C(═O)R C2 , —C(═O)OR C1 , —C(═O)SR C1 , —C(═O)N(R C1 ) 2 , —S(═O) 2 R C2 , —S(═O) 2 OR C1 , —P(═O) 2 R C2 , —P(═O) 2 OR C1 , —P(═O)(OR C1 ) 2 , —P(═O)(R C2 ) 2 , or —P(═O)(R C2 )(OR C1 ); 
 each occurrence of R B1  and R C1  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom; or two R B1  groups and/or two R C1  groups are joined to form an substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; 
 each occurrence of R B2  and R C2  is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and 
 R 6  is substituted or unsubstituted C 1 -C 6 alkyl. 
 
     
     
         7 . The method of  claim 6 , wherein the compound: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         8 - 9 . (canceled) 
     
     
         10 . The method of  claim 6 , wherein the bacterial infection is an  Escherichia coli, Pseudomonas aeruginosa, Vibrio cholerae , methicillin-resistant  Staphylococcus aureus , or  Mycobacterium tuberculosis  infection. 
     
     
         11 - 15 . (canceled) 
     
     
         16 . A method of treating a bacterial infection in a subject comprising administering an effective amount of a compound of Formula (IV): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, to the subject; 
       wherein:
 each occurrence of R 7 , R 8 , and R 9  is independently hydrogen or halogen; 
 each occurrence of R D1 , R D2 , R D3 , and R D4  is independently hydrogen, substituted or unsubstituted C 1-3  alkyl, —C(═O)R D6 , —C(═O)OR D5 , —C(═O)SR D5 , —C(═O)N(R D5 ) 2 , —S(═O) 2 R D6 , —S(═O) 2 OR D5 , —P(═O) 2 R D6 , —P(═O) 2 OR D5 , —P(═O)(OR D5 ) 2 , —P(═O)(R D6 ) 2 , or —P(═O)(R D6 )(OR D5 ); 
 each occurrence of R D5  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom; or two R D5  groups are joined to form an substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; 
 each occurrence of R D6  is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 10  is a group of formula: 
 
       
         
           
           
               
               
           
         
       
       wherein each instance of R 11a , R 11b , R 12a , R 12b , R 13a , and R 13b  is independently hydrogen, substituted or unsubstituted C 1-3  alkyl, or halogen;
 R 14  is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R E  is hydrogen, substituted or unsubstituted C 1-3  alkyl, —C(═O)R E2 , —C(═O)OR E1 , —C(═O)SR E1 , —C(═O)N(R E1 ) 2 , —S(═O) 2 R E2 , —S(═O) 2 OR E1 , —P(═O) 2 R E2 , —P(═O) 2 OR E1 , —P(═O)(OR E1 ) 2 , —P(═O)(R E2 ) 2 , or —P(═O)(R E2 )(OR E1 ); 
 each occurrence of R E1  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom; or two R E1  groups are joined to form an substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; 
 R E2  is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R F  is hydrogen, substituted or unsubstituted C 1-3  alkyl, —C(═O)R F2 , —C(═O)OR F1 , —C(═O)SR F1 , —C(═O)N(R F1 ) 2 , —S(═O) 2 R F2 , —S(═O) 2 OR F1 , —P(═O) 2 R F2 , —P(═O) 2 OR F1 , —P(═O)(OR F1 ) 2 , —P(═O)(R F2 ) 2 , or —P(═O)(R F2 )(OR F1 ); 
 each occurrence of R F1  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom; or two R F1  groups are joined to form an substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; and 
 R F2  is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 
 
     
     
         17 . The method of  claim 16 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         18 - 19 . (canceled) 
     
     
         20 . The method of  claim 16 , wherein the bacterial infection is an  Escherichia coli, Pseudomonas aeruginosa, Vibrio cholerae , methicillin-resistant  Staphylococcus aureus , or  Mycobacterium tuberculosis  infection. 
     
     
         21 . A method of identifying an inhibitor of bacterial sugar fermentation in a bacterial strain, the method comprising:
 (a) combining a candidate compound and a bacterial strain in which sugar transport depends on the phosphoenolpyruvate phosphotransferase system thereby producing a combination;   (b) culturing the combination in media comprising a sugar and one or more pH indicators under conditions appropriate for sugar fermentation by the bacterial strain; and   (c) determining if sugar fermentation occurs in the combination cultured in (b), wherein if sugar fermentation does not occur or is reduced in the combination cultured in (b), relative to the extent to which fermentation occurs under the same conditions except that the candidate compound is not present, the candidate compound is an inhibitor of bacterial sugar fermentation.   
     
     
         22 . The method of  claim 21 , wherein the method comprises at least two pH indicators. 
     
     
         23 . The method of  claim 21 , wherein the one or more pH indicators are protonated at about a pH <7.1. 
     
     
         24 . The method of  claim 21 , wherein at least one pH indicator is deprotonated at about a pH between 7.1 and 8.0. 
     
     
         25 . The method of  claim 21 , wherein at least one pH indicator is protonated at about a pH between 7.1 and 8.0. 
     
     
         26 . The method of  claim 21 , wherein at least one pH indicator is deprotonated at about a pH >8.0. 
     
     
         27 . The method of  claim 21 , wherein method comprises bromothymol blue and thymol blue as pH indicators. 
     
     
         28 . The method of  claim 21 , wherein the sugar is sucrose. 
     
     
         29 . The method of  claim 21 , wherein the candidate compound is a compound of Formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; 
       wherein:
 each occurrence of R 1 , R 2 , R 4a , and R 4b , is independently hydrogen or halogen; 
 R A  is hydrogen, substituted or unsubstituted C 1-3 alkyl, —C(═O)R A2 , —C(═O)OR A1 , —C(═O)SR A1 , —C(═O)N(R A1 ) 2 , —S(═O) 2 R A1 , —S(═O) 2 OR A1 , —P(═O) 2 R A2 , —P(═O)OR A1 , —P(═O)(OR A1 ) 2 , —P(═O)(R A2 ) 2 , or —P(═O)(R A2 )(OR A1 ); 
 R B  is hydrogen, substituted or unsubstituted C 1-3  alkyl, —C(═O)R B2 , —C(═O)OR B1 , —C(═O)SR B1 , —C(═O)N(R B1 ) 2 , —S(═O) 2 R B2 , —S(═O) 2 OR B1 , —P(═O) 2 R B2 , —P(═O) 2 OR B1 , —P(═O)(OR B1 ) 2 , —P(═O)(R B2 ) 2 , or —P(═O)(R B2 )(OR B1 ); 
 R C  is hydrogen, substituted or unsubstituted C 1-3  alkyl, —C(═O)R C2 , —C(═O)OR C1 , —C(═O)SR C1 , —C(═O)N(R C1 ) 2 , —S(═O) 2 R C2 , —S(═O) 2 OR C1 , —P(═O) 2 R C2 , —P(═O) 2 R C1 , —P(═O)(OR C1 ) 2 , —P(═O)(R C2 ) 2 , or —P(═O)(R C2 )(OR C1 ); 
 each occurrence of R A1 , R B1 , and R C1  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom; or two R A1  groups, two R B1  groups, and/or two R C1  groups are joined to form an substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; 
 each occurrence of R A2 , R B2 , and R C2  is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and 
 R 3  is substituted or unsubstituted C 2 -C 10 alkyl; or 
 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; 
       wherein:
 each occurrence of R 1 , R 2 , R 4a , R 4b , R 5a , and R 5b , is independently hydrogen or halogen; 
 R B  is hydrogen, substituted or unsubstituted C 1-3  alkyl, —C(═O)R B2 , —C(═O)OR B1 , —C(═O)SR B1 , —C(═O)N(R B1 ) 2 , —S(═O) 2 R B2 , —S(═O) 2 OR B1 , —P(═O) 2 R B2 , —P(═O) 2 OR B1 , —P(═O)(OR B1 ) 2 , —P(═O)(R B2 ) 2 , or —P(═O)(R B2 )(OR B1 ); 
 R C  is hydrogen, substituted or unsubstituted C 1-3  alkyl, —C(═O)R C2 , —C(═O)OR C1 , —C(═O)SR C1 , —C(═O)N(R C1 ) 2 , —S(═O) 2 R C2 , —S(═O) 2 OR C1 , —P(═O) 2 R C2 , —P(═O) 2 OR C1 , —P(═O)(OR C1 ) 2 , —P(═O)(R C2 ) 2 , or —P(═O)(R C2 )(OR C1 ); 
 each occurrence of R B1  and R C1  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom; or two R B1  groups and/or two R C1  groups are joined to form an substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; 
 each occurrence of R B2  and R C2  is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and 
 R 6  is substituted or unsubstituted C 1 -C 6 alkyl; or 
 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; 
       wherein:
 each occurrence of R 1 , R 2 , R 4a , and R 4b , is independently hydrogen or halogen; 
 R C  is hydrogen, substituted or unsubstituted C 1-3  alkyl, —C(═O)R C2 , —C(═O)OR C1 , —C(═O)SR C1 , —C(═O)N(R C1 ) 2 , —S(═O) 2 R C2 , —S(═O) 2 OR C1 , —P(═O)R C2 , —P(═O) 2 OR C1 , —P(═O)(OR C1 ) 2 , —P(═O)(R C2 ) 2 , or —P(═O)(R C2 )(OR C1 ); 
 each occurrence of R C1  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom; or two R C1  groups are joined to form an substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; 
 each occurrence of R C2  is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and 
 R 3  is substituted or unsubstituted C 2 -C 10 alkyl; or 
 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; 
       wherein:
 each occurrence of R 7 , R 8 , and R 9  is independently hydrogen or halogen; 
 each occurrence of R D1 , R D2 , R D3 , and R D4  is independently hydrogen, substituted or unsubstituted C 1-3  alkyl, —C(═O)R D6 , —C(═O)OR D5 , —C(═O)SR D5 , —C(═O)N(R D5 ) 2 , —S(═O)R D6 , —S(O) 2 OR D5 , —P(O) 2 R D6 , —P(═O) 2 OR D5 , —P(═O)(OR D5 ) 2 , —P(═O)(R D6 ) 2 , or —P(═O)(R D6 )(OR D5 ); 
 each occurrence of R D5  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom; or two R D5  groups are joined to form an substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; 
 each occurrence of R D6  is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 10  is a group of formula: 
 
       
         
           
           
               
               
           
         
       
       wherein each instance of R 11a , R 11b , R 12a , R 12b , R 13a , and R 13b  is independently hydrogen, substituted or unsubstituted C 1-3  alkyl, or halogen;
 R 14  is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R E  is hydrogen, substituted or unsubstituted C 1-3  alkyl, —C(═O)R E2 , —C(═O)OR E1 , —C(═O)SR E1 , —C(═O)N(R E1 ) 2 , —S(═O) 2 R E2 , —S(═O) 2 OR E1 , —P(═O)R E2 , —P(═O) 2 OR E1 , —P(═O)(OR E1 ) 2 , —P(═O)(R E2 ) 2 , or —P(═O)(R E2 )(OR E1 ); 
 each occurrence of R E1  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom; or two R E1  groups are joined to form an substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; 
 R E2  is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R F  is hydrogen, substituted or unsubstituted C 1-3  alkyl, —C(═O)R F2 , —C(═O)OR F1 , —C(═O)SR F1 , —C(═O)N(R F1 ) 2 , —S(O) 2 R F2 , —S(═O) 2 OR F1 , —P(═O) 2 R F2 , —P(═O) 2 OR F1 , —P(═O)(OR F1 ) 2 , —P(═O)(R F2 ) 2 , or —P(═O)(R F2 )(OR F1 ); 
 each occurrence of R F1  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom; or two R F1  groups are joined to form an substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; and 
 R F2  is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 
 
     
     
         30 . The method of  claim 21 , wherein the bacterial strain is  Escherichia coli, Pseudomonas aeruginosa, Vibrio cholerae , methicillin-resistant  Staphylococcus aureus , or  Mycobacterium tuberculosis.    
     
     
         31 . The method of  claim 6 , wherein each occurrence of R 1 , R 2 , R 4a , R 4b , R 5a , and R 5b  is hydrogen. 
     
     
         32 . The method of  claim 6 , wherein R B  is hydrogen. 
     
     
         33 . The method of  claim 6 , wherein R C  is hydrogen. 
     
     
         34 . The method of  claim 6 , wherein R 6  is unsubstituted C 1 -C 6 alkyl.