JAC Advance Access published online on March 13, 2003
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkg170
© 2003 by The British Society for Antimicrobial Chemotherapy
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Original article
1 School of Biological Sciences,
University of Wales Bangor, Gwynedd LL57 2UW, UK
* Corresponding author. E-mail: j.w.payne{at}bangor.ac.uk.
Received 3 December 2002
; revised 18 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
Structure-activity relationships for a
series of peptidomimetic antimicrobial prodrugs containing glutamine
analogues
awomir Milewski 2,
2 Department of Pharmaceutical Technology
and Biochemistry, Technical University of Gda
sk, Gdask,
80-952, Poland
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