Muraymycin A1
Muraymycins are a structurally unique family of aminoribosyluridyl peptide natural products originally isolated from Streptomyces sp. NRRL 30471. 19 congeners, designated muraymycins A1–A5, B1–B7, C1–C4, and D1–D3 were reported.[1] Subsequently, three additional analogues, muraymycins B8, B9, and C6, were reported from mutant strains of Streptomyces sp. NRRL 30473.[2] These compounds attracted considerable attention because of their potent antibacterial activity and their structurally distinct nucleoside-peptide framework, which differs substantially from classical antibacterial scaffolds. Among the reported congeners, muraymycin A1 emerged as the most potent analogue, demonstrating significant efficacy in a Staphylococcus aureus mouse infection model with an ED₅₀ value of 1.1 mg/kg.
Muraymycin A1 exerts its antibacterial activity through inhibition of translocase I (MraY/MurX), an essential phosphotransferase involved in the first membrane-associated step of bacterial peptidoglycan biosynthesis. MraY catalyzes transfer of phospho-MurNAc-pentapeptide onto undecaprenyl phosphate to generate lipid I, a critical precursor in bacterial cell wall assembly. Because MraY is indispensable for bacterial viability and absent in mammalian cells, muraymycins have historically been investigated primarily as antibacterial agents. However, increasing structural and mechanistic similarities between bacterial MraY and the mammalian paralog DPAGT1 (dolichyl-phosphate N-acetylglucosamine phosphotransferase 1) prompted renewed interest in the broader biological activities of these nucleoside natural products. DPAGT1 catalyzes the first committed step of the eukaryotic N-glycosylation pathway, initiating synthesis of dolichol-linked oligosaccharides required for maturation and trafficking of membrane and secreted glycoproteins.[3]
Tunicamycin V, the prototypical natural product inhibitor of DPAGT1, has long been utilized as a chemical probe to induce endoplasmic reticulum (ER) stress and unfolded protein response (UPR) signaling in mammalian cells. Inhibition of DPAGT1 by tunicamycin disrupts protein N-glycosylation, resulting in accumulation of misfolded glycoproteins within the ER lumen and the subsequent activation of ER stress pathways. Consequently, tunicamycin has become a widely used experimental tool in cancer biology, apoptosis research, and cellular stress signaling studies. However, the pharmacological utility of tunicamycin V is severely limited by its pronounced non-selective cytotoxicity. In addition to DPAGT1 inhibition, tunicamycin V exhibits substantial membrane-disruptive activity, producing rapid cell death in both malignant and nontransformed cells at low micromolar or submicromolar concentrations. This off-target toxicity has historically contributed to the assumption that DPAGT1 inhibition itself is intrinsically incompatible with selective anticancer therapy.[4]
Importantly, muraymycin A1 possesses several structural features reminiscent of tunicamycin V, including an aminoglycoside-containing uridine core linked to a long lipophilic side chain. These similarities raised the possibility that muraymycin A1 may also interact with DPAGT1 while potentially avoiding the severe cytotoxic liabilities associated with tunicamycins. To investigate this hypothesis, synthetic muraymycin A1 was evaluated for DPAGT1 inhibitory activity in direct comparison with tunicamycin V. Remarkably, muraymycin A1 inhibited DPAGT1 with greater than eight-fold higher potency than tunicamycin V, demonstrating that the muraymycin scaffold is highly compatible with productive interaction at the DPAGT1 active site.
Despite this enhanced enzyme inhibitory potency, muraymycin A1 displayed a dramatically improved cellular selectivity profile. Muraymycin A1 exhibited potent antiproliferative activity against multiple DPAGT1-dependent cancer cell lines, while showing no detectable cytotoxicity toward nontransformed mammalian cells at high concentrations under the tested conditions. This striking separation between antiproliferative activity and nonspecific cytotoxicity strongly suggests that selective inhibition of DPAGT1 can suppress cancer cell growth without inducing the catastrophic membrane damage associated with tunicamycin V.
References
- ↑ McDonald LA, Barbieri LR, Carter GT, Lenoy E, Lotvin J, Petersen PJ, Siegel MM, Singh G, Williamson RT (September 2002). "Structures of the Muraymycins, Novel Peptidoglycan Biosynthesis Inhibitors". J. Am. Chem. Soc. 124 (35): 10260–10261. PMID 12197711. Text " doi: 10.1021/ja017748h " ignored (help)
- ↑ Cui Z, Wang X, Koppermann S, Thorson JS, Ducho C, Van Lanen S (September 2018). "Antibacterial Muraymycins from Mutant Strains of Streptomyces sp. NRRL 30471". J. Nat. Prod. 81 (4): 942–948. PMID PMC6434714 Check
|pmid=value (help). Text " doi: 10.1021/acs.jnatprod.7b01054 " ignored (help); Vancouver style error: punctuation (help) - ↑ Kurosu M, Mitachi K (October 2025). "DPAGT1-Perspective as an Anticancer Drug Target". Molecules. 30 (20): 4049. PMID 41157066 Check
|pmid=value (help). Text " doi: 10.3390/molecules30204049 " ignored (help) - ↑ Mitachi K, Daria D, Kirsh JM, Effah W, Narayanan R, Clemons W M, Kurosu M (2026). "New Insights of Muraymycin A1 and Its Analogs as DPAGT1 Inhibitors". Bioorg. Chem. 169: 109402. Text " https://doi.org/10.1016/j.bioorg.2025.109402 " ignored (help); Vancouver style error: initials (help)
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