Tunicamycins (TUN) are inhibitors of the UDP-HexNAc: polyprenol-P HexNAc-1-P transferase family of enzymes, which initiate the biosynthesis of bacterial peptidoglycan and catalyze the first step in eukaryotic protein N-glycosylation. The TUN are therefore general and potent toxins to both eukaryotes and prokaryotes. Screening a library of synthetic TUN against Bacillus and yeast identified TUN that are antibacterial, but have significantly reduced eukaryotic toxicity. One of these (Tun-15:0) differs from the native TUN control only by the lack of the conjugated double bond in the tunicaminyl N-acyl group. Tun-15:0 also showed reduced inhibition for protein N-glycosylation in a Pichia-based bioassay. Natural TUN was subsequently modified by chemically reducing the N-acyl double bond (TunR1) or both the N-acyl and uridyl double bonds (TunR2). TunR1 and TunR2 retain their antibacterial activity, but with considerably reduced eukaryotic toxicity. In protein N-glycosylation bioassays, TunR1 is a less potent inhibitor than native TUN and TunR2 is entirely inactive. Importantly, the less toxic TunR1 and TunR2 both enhance the antibacterial activity of β-lactams: oxacillin by 32- to 64-fold, comparable with native TUN, and with similar enhancements for methicillin and penicillin G. Hence, the modified TUNs, TunR1 and TunR2, are potentially important as less-toxic synergistic enhancers of the β-lactams.

中文翻译：

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具有降低的真核毒性的修饰的衣霉素，可增强β-内酰胺的抗菌活性。

衣霉素（TUN）是UDP-HexNAc：聚prenol-P HexNAc-1-P转移酶家族的抑制剂，可启动细菌肽聚糖的生物合成并催化真核蛋白N-糖基化的第一步。因此，TUN是真核生物和原核生物的一般和有效毒素。筛选针对芽孢杆菌和酵母的合成TUN文库可确定TUN具有抗菌作用，但具有显着降低的真核毒性。其中一个（Tun-15：0）与天然TUN对照的不同之处仅在于衣甲胺基N-酰基缺少共轭双键。在基于毕赤酵母的生物测定中，Tun-15：0还显示出对蛋白质N-糖基化的抑制作用降低。天然TUN随后通过化学还原N-酰基双键（TunR1）或N-酰基和尿嘧啶双键（TunR2）进行修饰。TunR1和TunR2保留其抗菌活性，但真核毒性大大降低。在蛋白质N-糖基化生物测定中，与天然TUN相比，TunR1的抑制作用较弱，而TunR2则完全没有活性。重要的是，毒性较低的TunR1和TunR2均可将β-内酰胺类药物：奥沙西林的抗菌活性提高32到64倍，与天然TUN相当，对甲氧西林和青霉素G的增强作用也相似。因此，修饰的TUN，TunR1和TunR2作为低毒性的β-内酰胺类协同增效剂，可能具有重要意义。