SummaryMuraymycins are a promising class of antimicrobial natural products. These uridine-derived nucleoside-peptide antibiotics inhibit the bacterial membrane protein translocase I (MraY), a key enzyme in the intracellular part of peptidoglycan biosynthesis. This review describes the structures of naturally occurring muraymycins, their mode of action, synthetic access to muraymycins and their analogues, some structure–activity relationship (SAR) studies and first insights into muraymycin biosynthesis. It therefore provides an overview on the current state of research, as well as an outlook on possible future developments in this field.

Naturally occurring muraymycin nucleoside antibiotics represent a promising class of novel antimicrobials as they inhibit MraY, an enzyme involved in bacterial cell wall biosynthesis. The synthesis of muraymycins and their analogues is challenging as it involves multi‐step routes, thus hampering detailed structure‐activity relationship (SAR) studies. In this work, we report a novel solid phase‐based synthetic strategy for accessing muraymycin analogues via a modular approach, thereby enabling a more efficient access to structural variations, particularly of the muraymycin peptide moiety. The efficiency of this new method was exemplified in an alanine scan of the peptide unit. The inhibitory in vitro activities of the resultant analogues towards MraY provided novel SAR insights. Overall, this new synthetic method for the preparation of muraymycin analogues might support the development of these antibacterial agents towards potential drug candidates.

Naturally occurring nucleoside-peptide antibiotics such as muraymycins or caprazamycins are of major interest for the development of novel antibacterial agents. However, the synthesis of new analogues of these natural products for structure–activity relationship (SAR) studies is challenging. In our synthetic efforts towards a muraymycin-derived nucleoside building block suitable for attachment to a solid support, we came across an interesting side product. This compound resulted from an undesired Fmoc deprotection with subsequent cyclization, thus furnishing a remarkable caprazamycin-like seven-membered diazepanone ring.

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