Inhibitors for the tRNA dependent ligase MurM from streptococcus pneumoniae

The FemABX family of peptide ligases comprises enzymes responsible for the branching of peptidoglycan peptide part. In particular, MurM from the bacterium S. pneu11loniae is responsible for the transfer of L-alanine or L-serine from tRNA to the lysine side chain of the peptidoglycan precursor Lipid 2. MurM, and the members of the FemABX family, have been proven by genetic experiments to be essential for the development of antibiotic resistance in pathogenic bacteria and in some cases for the life of the cell itself, and therefore they constitute a new range of targets for the development of narrow spectrum antibiotics against highly resistant strains of pathogens. Inhibitors of this class of enzymes might act as efficient antibiotics, in synergy with ~-lactams, causing cell lysis. During the course of this research project, a series of S. pneu11loniae MurM inhibitors have been designed, synthesised and tested. The design of MurM inhibitors was based on the transition state analogue approach and two generations of organophosphorus derivatives have been synthesised. The first was based on a I-amino phosphonamide moiety, functionalised with simple alkyl/aryl groups; the second was a series of adenosine or 2'-deoxyadenosine I-amino phosphonates. The activity of the potential inhibitors was assayed with a radiochemical assay which monitors the transfer of a radiolabelled amino acid from tRNA to Lipid 2 in the presence ofMurM. The first generation of inhibitors was inactive on MurM while in the second generation, 2'-(1-amino ethyl phosphonyl) adenosine and 3'-(l-amino ethyl phosphonyl) 2'-deoxyadenosine showed inhibitory activity on MurM, with ICso values of780 JlM and 100 JlM respectively.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Adenosine phosphonate inhibitors of lipid II: Alanyl tRNA ligase MurM from Streptococcus pneumoniae

Adenosine and 2 '-deoxyadenosine phosphonate transition state analogues act as the first inhibitors for the MurMN/FemABX family of tRNA-dependent ligases implicated in high-level penicillin resistance in Gram-positive bacteria. (c) 2007 Elsevier Ltd. All rights reserved

Inhibition of tRNA-dependent ligase MurM from Streptococcus pneumoniae by phosphonate and sulfonamide inhibitors

Ligase MurM catalyses the addition of Ala from alanyl-tRNA(Ala), or Ser from seryl-tRNA(Ser), to lipid intermediate II in peptidoglycan biosynthesis in Streptococcus pneumoniae, and is a determinant of high-level penicillin resistance. Phosphorus-based transition state analogues were designed as inhibitors of the MurM-catalysed reaction. Phosphonamide analogues mimicking the attack of a lysine nucleophile upon Ala-tRNA(Ala) showed no inhibition of MurM, but adenosine 3'-phosphonate analogues showed inhibition of MurM, the most active being a 2'-deoxyadenosine analogue (IC50 100 mu M). Structure/function studies upon this analogue established that modi. cation of the amino group of the aminoalkylphosphonate resulted in loss of potency, and modi. cation of the adenosine 5'-hydroxyl group with either a t-butyl dimethyl silyl or a carbamate functional group resulted in loss of activity. A library of 48 aryl sulfonamides was also screened against MurM using a radiochemical assay, and two compounds showed sub-millimolar inhibition. These compounds are the first small molecule inhibitors of the Fem ligase family of peptidyltransferases found in Gram-positive bacteria. (C) 2009 Elsevier Ltd. All rights reserved