Elucidating the Structural Requirement of Uridylpeptide Antibiotics for Antibacterial Activity

The
synthesis and biological evaluation of analogues of uridylpeptide
antibiotics were described, and the molecular interaction between
the 3′-hydroxy analogue of mureidomycin A (3′-hydroxymureidomycin
A) and its target enzyme, phospho-MurNAc-pentapeptide transferase
(MraY), was analyzed in detail. The structure–activity relationship
(SAR) involving MraY inhibition suggests that the side chain at the
urea-dipeptide moiety does not affect the MraY inhibition. However,
the anti-Pseudomonas aeruginosa activity
is in great contrast and the urea-dipeptide motif is a key contributor.
It is also suggested that the nucleoside peptide permease NppA1A2BCD
is responsible for the transport of 3′-hydroxymureidomycin
A into the cytoplasm. A systematic SAR analysis of the urea-dipeptide
moiety of 3′-hydroxymureidomycin A was further conducted and
the antibacterial activity was determined. This study provides a guide
for the rational design of analogues based on uridylpeptide antibiotics.