Department of Pharmacy, Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2 3, 66123, Saarbrücken, Germany.
Chemistry. 2020 Dec 15;26(70):16875-16887. doi: 10.1002/chem.202003387. Epub 2020 Nov 16.
To overcome bacterial resistances, the need for novel antimicrobial agents is urgent. The class of so-called nucleoside antibiotics furnishes promising candidates for the development of new antibiotics, as these compounds block a clinically unexploited bacterial target: the integral membrane protein MraY, a key enzyme in cell wall (peptidoglycan) biosynthesis. Nucleoside antibiotics exhibit remarkable structural diversity besides their uridine-derived core motifs. Some sub-classes also show specific selectivities towards different Gram-positive and Gram-negative bacteria, which are poorly understood so far. Herein, the synthesis of a novel hybrid structure is reported, derived from the 5'-defunctionalized uridine core moiety of muraymycins and the peptide chain of sansanmycin B, as a new scaffold for the development of antimicrobial agents. The reported muraymycin-sansanmycin hybrid scaffold showed nanomolar activity against the bacterial target enzyme MraY, but displayed no significant antibacterial activity against S. aureus, E. coli, and P. aeruginosa.
为了克服细菌耐药性，我们迫切需要新型抗菌药物。所谓的核苷类抗生素为开发新型抗生素提供了有希望的候选药物，因为这些化合物可以阻断一种临床上尚未开发的细菌靶标：整合膜蛋白 MraY，这是细胞壁（肽聚糖）生物合成的关键酶。除了其尿嘧啶衍生的核心基序外，核苷类抗生素还表现出显著的结构多样性。一些亚类对不同的革兰氏阳性菌和革兰氏阴性菌也表现出特定的选择性，但迄今为止了解甚少。在此，报道了一种新型杂合结构的合成，该结构源自 muraymycins 的 5'-去功能化尿嘧啶核心部分和 sansanmycin B 的肽链，作为开发抗菌药物的新支架。报道的 muraymycin-sansanmycin 杂合支架对细菌靶酶 MraY 具有纳摩尔级的活性，但对金黄色葡萄球菌、大肠杆菌和铜绿假单胞菌没有显著的抗菌活性。
