Structure-activity relationships for a series of peptidomimetic antimicrobial prodrugs containing glutamine analogues

Abstract

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.

The small RNA GlmY acts upstream of the sRNA GlmZ in the activation of glmS expression and is subject to regulation by polyadenylation in Escherichia coli

“…To address this question, we used Nva-FMDP, a derivative of N3-(4-methoxyfumaroyl)-L-2,3-diaminopropanoic acid. This compound selectively inhibits GlmS enzymatic activity in vivo (27) and thereby causes a decrease in the intracellular GlcN-6-P concentration, which leads to induction of glmS expression via accumulation of full-length GlmZ (4). To see whether the intracellular GlcN-6-P concentration also affects the amount of GlmY present in the cell, the wild-type strain was grown to exponential phase and after splitting of the culture, growth was continued in either the absence or presence of Nva-FMDP.…”

Feedback control of glucosamine‐6‐phosphate synthase GlmS expression depends on the small RNA GlmZ and involves the novel protein YhbJ in Escherichia coli

“…6A and B). Nva‐FMDP is a derivative of N3‐(4‐methoxyfumaroyl)‐ l ‐2,3‐diaminopropanoic acid (FMDP) and was shown to selectively inhibit GlmS activity (Marshall et al ., 2003). No deleterious effect of Nva‐FMDP on the growth could be observed (growth curves in Fig.…”

Structural Analysis of Bacterial ABC Transporter Inhibition by an Antibody Fragment

“…Rather, the logic behind this approach is that these targets may be suitable candidates for multiantigen vaccines. A very different preclinical strategy exploits the broad specificity of some peptide ABC importers to facilitate the uptake of antibacterial drugs that are covalently linked to natural transporter substrates (Marshall et al, 2003). This approach is likewise not founded on ABC transporter inhibition.…”