JAC Advance Access originally published online on March 13, 2003
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Journal of Antimicrobial Chemotherapy (2003) 51, 821-831
© 2003 The British Society for Antimicrobial Chemotherapy
Structure–activity relationships for a series of peptidomimetic antimicrobial prodrugs containing glutamine analogues
awomir Milewski21 School of Biological Sciences, University of Wales Bangor, Gwynedd LL57 2UW, UK; 2 Department of Pharmaceutical Technology and Biochemistry, Technical University of Gdaásk, Gdaásk, 80-952, Poland
Received 3 December 2002; returned 18 January 2003; revised 21 January 2003; accepted 21 January 2003
Synthetic glutamine analogues such as N3-(4-methoxyfumaroyl)-L-2,3-diaminopropanoic acid (FMDP) inhibit purified glucosamine-6-phosphate synthase, an intracellular enzyme that is essential for microbial cell wall synthesis, but they are inactive against intact organisms because they cannot enter the cell. However, when the analogues are linked to a peptide they can be actively transported, and FMDP peptidomimetics show broad-spectrum antimicrobial activity. To characterize this process in more detail, the antibacterial activities of various synthetic peptidomimetics containing glutamine analogues have been determined against isogenic strains of Escherichia coli in which one or more of its three peptide transporters Dpp, Opp and Tpp have been mutated. In addition, their affinities for DppA and OppA, the binding-protein components of the transporters, have been measured. In general, antibacterial activities against the various transport mutants correlated with binding to DppA and OppA. Xaa-FMDP compounds have greater activities than FMDP-Xaa analogues. To explore structure–activity relationships for the peptidomimetics, molecular modelling was used to determine the conformational forms they adopt in solution. The relative bioactivities of the peptidomimetics correlated with the percentage of conformers that had backbone torsions matching those previously defined for the molecular recognition templates of the peptide transporters. However, the large size of the N-terminal residue in the FMDP-Xaa analogues appears to interfere with transport and thus to limit antibacterial activity. Overall, the results provide the structural rationale for the identification in silico of analogues with optimal bioactivities, which decreases the need for extensive chemical syntheses and testing.
Keywords: cell wall biosynthesis, peptide transport, molecular modelling, molecular recognition
* Corresponding author. Tel: +44-1248-382349; Fax: +44-1248-370731; E-mail: j.w.payne{at}bangor.ac.uk
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