Exploring the Active Site of the Antibacterial Target
MraY by Modified Tunicamycins
Posted on 2020-11-09 - 16:04
The
alarming growth of antibiotic resistance that is currently
ongoing is a serious threat to human health. One of the most promising
novel antibiotic targets is MraY (phospho-MurNAc-pentapeptide-transferase),
an essential enzyme in bacterial cell wall synthesis. Through recent
advances in biochemical research, there is now structural information
available for MraY, and for its human homologue GPT (GlcNAc-1-P-transferase),
that opens up exciting possibilities for structure-based drug design.
The antibiotic compound tunicamycin is a natural product inhibitor
of MraY that is also toxic to eukaryotes through its binding to GPT.
In this work, we have used tunicamycin and modified versions of tunicamycin
as tool compounds to explore the active site of MraY and to gain further
insight into what determines inhibitor potency. We have investigated
tunicamycin variants where the following motifs have been modified:
the length and branching of the tunicamycin fatty acyl chain, the
saturation of the fatty acyl chain, the 6″-hydroxyl group of
the GlcNAc ring, and the ring structure of the uracil motif. The compounds
are analyzed in terms of how potently they bind to MraY, inhibit the
activity of the enzyme, and affect the protein thermal stability.
Finally, we rationalize these results in the context of the protein
structures of MraY and GPT.
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Hering, Jenny; Dunevall, Elin; Snijder, Arjan; Eriksson, Per-Olof; Jackson, Michael A.; Hartman, Trina M.; et al. (2020). Exploring the Active Site of the Antibacterial Target
MraY by Modified Tunicamycins. ACS Publications. Collection. https://doi.org/10.1021/acschembio.0c00423
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AUTHORS (11)
JH
Jenny Hering
ED
Elin Dunevall
AS
Arjan Snijder
PE
Per-Olof Eriksson
MJ
Michael A. Jackson
TH
Trina M. Hartman
RT
Ran Ting
HC
Hongming Chen
NP
Neil P. J. Price
GB
Gisela Brändén
ME
Margareta Ek