Structural requirement of tunicamycin V for MraY inhibition

Synthesis and biological evaluation of a MraY selective analogue of tunicamycins

“…These results in conjunction with our structure-activity relationship study with truncated analogues [18] make a potential modification to the GlcNAc moiety feasible to improve the biological activity for future molecular design. Although the inhibitory activity of 2 against MraY from Aquifex aeolicus (MraYAA) and human GTP was evaluated, its inhibitory activity against MraY from bacterial pathogens, cytotoxicity against human cells, and antibacterial activity have not yet been investigated.…”

Bacillus subtilis natto Derivatives Inhibit Enterococcal Biofilm Formation via Restructuring of the Cell Envelope

“…Notably, the bacterial cell envelope synthetic process has been reported to be the major target for many antibacterial agents ( McCallum et al, 2011 ). Many antibiotics act by blocking or disrupting bacterial peptidoglycan biosynthesis, such as fosfomycin, which inhibits MurA ( Hashemian et al, 2019 ), and tunicamycin, which inhibits bacterial phospho-N-acetylmuramic acid (MurNAc)-pentapeptide translocase (MraY; Yamamoto et al, 2019 ). Furthermore, because maintenance of cell wall homeostasis and growth in low-G+C Gram-positive bacteria is essential, the WalK/WalR two-component system has been proposed as a novel target for antibacterial agents that are effective against multidrug-resistant bacteria, including MRSA and vancomycin-resistant E. faecalis ( Fabret and Hoch, 1998 ; Gotoh et al, 2010 ).…”

Mechanism of action of nucleoside antibacterial natural product antibiotics

“…The biosynthetic gene cluster for the tunicamycin antibiotics has been identified in Streptomyces chartreusis [6], and the biosynthetic pathway has been shown to involve an unusual radical SAM enzyme TunM in the assembly of the tunicamine sugar [7]. A total synthesis of tunicamycin V was reported in 2017 by Ichikawa and co-workers [8], which has enabled the synthesis of tunicamycin analogues for structure-activity study [9]. A lipidtruncated analogue and an analogue lacking the GlcNAc sugar both lost 1000-fold in MraY inhibition activity but retained some enzyme inhibition, while an analogue lacking the nucleoside base was completely inactive [9].…”

“…A total synthesis of tunicamycin V was reported in 2017 by Ichikawa and co-workers [8], which has enabled the synthesis of tunicamycin analogues for structure-activity study [9]. A lipidtruncated analogue and an analogue lacking the GlcNAc sugar both lost 1000-fold in MraY inhibition activity but retained some enzyme inhibition, while an analogue lacking the nucleoside base was completely inactive [9]. The preseence of the uracil base has been shown to be required in other nucleoside antibiotic families [3,4], which can be rationalised by the MraY structural studies described in Section 2.2.…”