Allen N E, Hobbs J N, Alborn W E
Lilly Research Laboratories, Indianapolis, Indiana 46285.
Antimicrob Agents Chemother. 1987 Jul;31(7):1093-9. doi: 10.1128/AAC.31.7.1093.
LY146032, a cyclic lipopeptide antibiotic, is an inhibitor of cell wall peptidoglycan biosynthesis in gram-positive bacteria. Although LY146032 at relatively high concentrations inhibited the in vitro polymerization of UDP-linked sugar precursors, inhibition of cell wall formation in intact Staphylococcus aureus and Bacillus megaterium cells did not lead to the accumulation of UDP-N-acetyl-muramyl (MurNAc)-peptide(s). Experiments that measured formation of UDP-MurNAc-peptides revealed that LY146032 inhibited the formation of these nucleotide-linked intermediates. This antibiotic had a disruptive effect on membrane permeability as evidenced by the loss of intracellular potassium immediately after exposure to the drug. The lack of any major disruption of the phosphoenolpyruvate:sugar phosphotransferase system indicated that the membrane is not likely a lethal target for this antibiotic. The findings are consistent with a mechanism by which LY146032 inhibits the formation of precursor molecules utilized in peptidoglycan biosynthesis. The observed membrane effects likely result from transit of the inhibitor to its lethal target site.
LY146032是一种环脂肽抗生素，是革兰氏阳性菌细胞壁肽聚糖生物合成的抑制剂。尽管相对高浓度的LY146032会抑制UDP连接的糖前体的体外聚合，但在完整的金黄色葡萄球菌和巨大芽孢杆菌细胞中抑制细胞壁形成并未导致UDP-N-乙酰胞壁酰（MurNAc）肽的积累。测量UDP-MurNAc-肽形成的实验表明，LY146032抑制了这些核苷酸连接中间体的形成。这种抗生素对膜通透性有破坏作用，暴露于该药物后细胞内钾离子立即流失就证明了这一点。磷酸烯醇丙酮酸：糖磷酸转移酶系统没有任何重大破坏，这表明膜不太可能是这种抗生素的致死靶点。这些发现与LY146032抑制肽聚糖生物合成中使用的前体分子形成的机制一致。观察到的膜效应可能是抑制剂转运到其致死靶点部位的结果。
