Peptide deformylase inhibitors as novel antibiotics

Abstract

A macrocyclic peptide deformylase (PDF) inhibitor comprising a peptide or peptide mimetic having three residues, P 1′, P 2′, and P 3′, wherein P 2′ connects P 1′ and P 3′, wherein P 1′ and P 3′ each have a side chain, and wherein the side chains on P 1′ and P 3′ are crosslinked to form the macrocyclic PDF inhibitor. The side chains of P 1′ and P 3′ interact with the PDF active site, and preferably, P 2′ has a side chain that interacts with a solvent. Also provided are methods of inhibiting the growth of a bacterium, the methods comprising contacting the bacterium with an anti-bacterial effective amount of the inventive macrocyclic PDF inhibitor. Additionally, a method of treating a bacterial infection in a subject comprising administering an effective amount of a macrocyclic PDF inhibitor to a subject in need of treatment. Additionally, methods of preparing macrocyclic PDF inhibitors comprising a) choosing an acyclic base molecule, having at least some PDF inhibitory activity, the acyclic base molecule having a first residue having a first side chain that interacts with the PDF active site and a second residue having a second that interacts with the PDF active site; and b) crosslinking the first side chain and the second side chain to form a macrocyclic PDF inhibitor.

1 . A composition of formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 Y is selected from the group consisting of N-formylhydroxylamine and hydroxamate; 
 Z is selected from the group consisting of H, C 1 -C 10  alkyl, C 1 -C 10  alkenyl, C 1 -C 10  alkynyl, a side chain of any naturally occurring L-amino acid, and a side chain of any D-amino acid; and 
 n is from 1 to 13. 
 
     
     
         2 . The composition of  claim 1  wherein Y is N-formylhydroxylamine. 
     
     
         3 . The composition of  claim 1  wherein Y is hydroxamate. 
     
     
         4 . The composition of  claim 1  wherein Z is selected from the group consisting of H, C 1 -C 10  alkyl, C 1 -C 10  alkenyl, and C 1 -C 10  alkynyl. 
     
     
         5 . The composition of  claim 1  wherein Z is selected from the group consisting of a side chain of any naturally occurring L-amino acid and a side chain of any D-amino acid. 
     
     
         6 . The composition of  claim 5  wherein Z is a side chain of any naturally occurring L-amino acid. 
     
     
         7 . The composition of  claim 6  wherein the naturally occurring L-amino acid is selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, methionine, proline, phenylalanine, tryptophan, serine, threonine, asparagine, glutamine, tyrosine, cysteine, lysine, arginine, histidine, aspartic acid, and glutamic acid. 
     
     
         8 . The composition of  claim 5  wherein Z is a side chain of any D-amino acid. 
     
     
         9 . The composition of  claim 1  wherein n is 1 to 8. 
     
     
         10 . The composition of  claim 9  wherein n is 3 to 5. 
     
     
         11 . The composition of  claim 1  wherein the composition is a macrocyclic peptide deformylase (PDF) inhibitor. 
     
     
         12 . A method of treating a bacterial infection in a subject comprising administering to a subject an effective amount of a composition of formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 Y is selected from the group consisting of N-formylhydroxylamine and hydroxamate; 
 Z is selected from the group consisting of H, C 1 -C 10  alkyl, C 1 -C 10  alkenyl, C 1 -C 10  alkynyl, a side chain of any naturally occurring L-amino acid, and a side chain of any D-amino acid; and 
 n is from 1 to 13. 
 
     
     
         13 . The method of  claim 12  wherein n is 1 to 8. 
     
     
         14 . The method of  claim 13  wherein n is 3 to 5. 
     
     
         15 . The method of  claim 12  wherein the bacterial infection is a drug-sensitive bacterial infection. 
     
     
         16 . The method of  claim 12  wherein the bacterial infection is a drug-resistant bacterial infection. 
     
     
         17 . The method of  claim 12  wherein the subject is a human. 
     
     
         18 . A method of inhibiting the growth of a bacterium comprising contacting the bacterium with an anti-bacterially effective amount of a composition of formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 Y is selected from the group consisting of N-formylhydroxylamine and hydroxamate; 
 Z is selected from the group consisting of H, C 1 -C 10  alkyl, C 1 -C 10  alkenyl, C 1 -C 10  alkynyl, a side chain of any naturally occurring L-amino acid, and a side chain of any D-amino acid; and 
 n is from 1 to 13. 
 
     
     
         19 . The method of  claim 18  wherein n is 1 to 8. 
     
     
         20 . The method of  claim 19  wherein n is 3 to 5.