Total Syntheses of Bulgecins A, B, and C and Their Bactericidal Potentiation of the β-Lactam Antibiotics.
Total Syntheses of Bulgecins A, B, and C and Their Bactericidal Potentiation of the β-Lactam Antibiotics.
复制标题
DOI：
10.1021/acsinfecdis.8b00105
复制
发表时间：
2018-06-08
影响因子：
5.3
通讯作者：
Mobashery S
中科院分区：
文献类型：
--
作者：
Tomoshige S;Dik DA;Akabane-Nakata M;Madukoma CS;Fisher JF;Shrout JD;Mobashery S
bulgecins 是革兰氏阴性细菌嗜酸副伯克霍尔德氏菌的亚氨基糖次级代谢物，也是细菌细胞壁生物合成和重塑的溶解性转糖基酶的抑制剂。 bulgecins 的活性与共生物合成的 β-内酰胺抗生素的机制密切相关。 β-内酰胺抑制青霉素结合蛋白，这种酶对细胞壁生物合成也至关重要。裂解性转糖基酶（bulgecin）和青霉素结合蛋白（β-内酰胺）活性的同时丧失导致隔膜细胞壁变形，在显微镜下观察到细菌细胞裂解前的凸起。我们描述了三种天然存在的 bulgecin 亚氨基糖的实际合成及其在一系列微生物学研究中的机理评估。这些研究确定了 bulgecin 在 β-内酰胺亚最低抑制浓度下对三种致病性革兰氏阴性菌的增强作用，并首次证实这种增强作用导致临床 β-内酰胺的杀菌功效显着增加。
The bulgecins are iminosaccharide secondary metabolites of the Gram-negative bacterium Paraburkholderia acidophila and inhibitors of lytic transglycosylases of bacterial cell-wall biosynthesis and remodeling. The activities of the bulgecins are intimately intertwined with the mechanism of a cobiosynthesized β-lactam antibiotic. β-Lactams inhibit the penicillin-binding proteins, enzymes also critical to cell-wall biosynthesis. The simultaneous loss of the lytic transglycosylase (by bulgecin) and penicillin-binding protein (by β-lactams) activities results in deformation of the septal cell wall, observed microscopically as a bulge preceding bacterial cell lysis. We describe a practical synthesis of the three naturally occurring bulgecin iminosaccharides and their mechanistic evaluation in a series of microbiological studies. These studies identify potentiation by the bulgecin at subminimum inhibitory concentrations of the β-lactam against three pathogenic Gram-negative bacteria and establish for the first time that this potentiation results in a significant increase in the bactericidal efficacy of a clinical β-lactam.