D-Alanyl-D-alanine dipeptide of bacterial peptidoglycan precursor (D-Ala-D-Ala)

The D-alanyl-D-alanine dipeptide is the terminal moiety of the pentapeptide stem in nascent bacterial peptidoglycan, essential for the structural integrity and viability of nearly all bacteria. This motif is synthesized in the cytoplasm by D-Ala-D-Ala ligase and incorporated into peptidoglycan precursors. The terminal D-Ala-D-Ala sequence is the target for DD-transpeptidase-mediated cross-linking during cell wall assembly. Multiple antibiotics—including glycopeptides (like vancomycin) and β-lactam drugs—exploit either direct binding to this motif or its molecular mimicry to inhibit cell wall synthesis, making it a central target in antibacterial therapy[2][6][5]. Modifications to this dipeptide, such as substitution with D-Ala-D-Lac or D-Ala-D-Ser, confer clinically significant antibiotic resistance.

Other names

D-Alanyl-D-alanineD-Ala-D-Ala terminusPeptidoglycan pentapeptide terminusMurein precursor dipeptide

Antibiotic binding to D-Ala-D-Ala: Glycopeptides (vancomycin, teicoplanin) bind the D-Ala-D-Ala terminus, blocking transpeptidation and preventing cross-linking of peptidoglycan, leading to bacterial cell death. - Inhibition of D-Ala-D-Ala synthesis: D-cycloserine inhibits D-alanine racemase and D-Ala-D-Ala ligase, reducing precursor availability. - Mimicry and competitive inhibition: β-lactam antibiotics structurally mimic D-Ala-D-Ala and irreversibly inhibit DD-transpeptidase enzymes required for cross-linking the peptidoglycan.