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- W1521664694 abstract "The widespread use of antibiotics has played a significant role in the emergence ofresistant bacteria. It is of great interest and need to develop novel, effective and safeantimicrobial therapeutics. The biosynthesis of bacterial cell wall peptidoglycan is anintricate process that has become a popular target for antibiotics. Lytic protein E ofBacteriophage ΦX174 was found to inhibit peptidoglycan biosynthesis via anunknown interaction with integral protein MraY. Genetic studies have revealed thatE-mediated lysis is dependent on the interaction between Phe288 of MraY and thetransmembrane segment of protein E.We have constructed an α-helical model for the predicted transmembrane interactionsbetween protein E and MraY and shown that favourable interactions can be formedbetween Phe288 and the RWXXW motif of protein E. In this thesis, analogues of theRWXXW motif were synthesised in solution and via solid phase peptide synthesisusing 2-chlorotrityl chloride resin as the polymeric support. The inhibitory activity ofthese analogues was determined on a continuous fluorescence assay againstmembrane bound MraY. Inhibition studies on site-directed mutants of E. coli MraYwere also conducted. Testing the inhibitory activity of RWXXW analogues providedcompelling information on the importance of protein E residues for the inhibition ofMraY. Peptides which contained a tryptophan residue were especially good inhibitorsof MraY presumably due to their interaction with Phe288. Mutation of Phe288 causeda dramatic decrease or complete loss to the inhibitory activity of peptides containingan aromatic residue.Some analogues also contained antibacterial activity across multiple strains ofbacteria including E. coli, B. subtilis and P. putida with MIC values as low as8μg/mL. To confirm if MraY was the target enzyme, E. coli cells overexpressingMraY were treated with RWXXW analogues. An increase in the MIC of RWXXWanalogues signified that the MraY was the lysis target.In the course of the project, we noticed that members of the UPA class of naturalproducts contained some structural features that are also found in the RWXXW motif.These natural products were tested for activity against site-directed mutants of E. coliMraY. Results showed that Phe288 plays some role in the inhibition of MraY bypacidamycin. This work identifies a promising target for the development of novelantimicrobial agents that is located on the outer face of the cytoplasmic membrane." @default.
- W1521664694 created "2016-06-24" @default.
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- W1521664694 date "2013-09-01" @default.
- W1521664694 modified "2023-09-23" @default.
- W1521664694 title "Interaction of translocase MraY with the antibacterial E protein from bacteriophage ΦX174" @default.
- W1521664694 hasPublicationYear "2013" @default.
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