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Title: Inhibitors for the tRNA dependent ligase MurM from streptococcus pneumoniae
Author: Cressina, Elena
ISNI:       0000 0001 3396 500X
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2007
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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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available