Allen N E, Hobbs J N, Nicas T I
Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
Antimicrob Agents Chemother. 1996 Oct;40(10):2356-62. doi: 10.1128/AAC.40.10.2356.
LY191145 is a p-chlorobenzyl derivative of LY264826 (A82846B) with activity against both vancomycin-susceptible and -resistant enterococci. Incorporation of L-[14C]lysine into peptidoglycan of intact vancomycin-susceptible and -resistant Enterococcus faecium was inhibited by LY191145 (50% inhibitory concentrations of 1 and 5 microgram/ml, respectively). Inhibition was accompanied by accumulation of UDP-muramyl-peptide precursors in the cytoplasm. This agent inhibited late-stage steps in peptidoglycan biosynthesis in permeabilized E. faecium when either the UDP-muramyl-pentapeptide precursor from vancomycin-susceptible E. faecium or the UDP-muramyl-pentadepsipeptide precursor from vancomycin-resistant E. faecium was used as a substrate. Inhibition of late-stage steps led to accumulation of an N-acetyl-[14C]glucosamine-labeled lipid intermediate indicative of inhibition of the transglycosylation step. Inhibition of peptidoglycan polymerization without affecting cross-linking in a particulate membrane-plus-wall-fragment assay from Aerococcus viridans was consistent with this explanation. The fact that inhibition of peptidoglycan biosynthesis by LY191145 was not readily antagonized by an excess of free acyl-D-alanyl-D-alanine or acyl-D-alanyl-D-lactate ligands indicates that the manner in which this compound inhibits transglycosylation may not be identical to that of vancomycin.
LY191145是LY264826（A82846B）的对氯苄基衍生物，对万古霉素敏感和耐药的肠球菌均有活性。LY191145可抑制L-[14C]赖氨酸掺入完整的万古霉素敏感和耐药屎肠球菌的肽聚糖中（50%抑制浓度分别为1和5微克/毫升）。抑制作用伴随着UDP-胞壁酰肽前体在细胞质中的积累。当使用来自万古霉素敏感屎肠球菌的UDP-胞壁酰五肽前体或来自万古霉素耐药屎肠球菌的UDP-胞壁酰五肽去甲肽前体作为底物时，该药物可抑制通透化屎肠球菌中肽聚糖生物合成的后期步骤。后期步骤的抑制导致一种N-乙酰-[14C]葡萄糖胺标记的脂质中间体积累，这表明转糖基化步骤受到抑制。在来自绿色气球菌的颗粒膜加细胞壁片段试验中，LY191145对肽聚糖聚合的抑制而不影响交联，这与上述解释一致。LY191145对肽聚糖生物合成的抑制作用不易被过量的游离酰基-D-丙氨酰-D-丙氨酸或酰基-D-丙氨酰-D-乳酸配体拮抗，这表明该化合物抑制转糖基化的方式可能与万古霉素不同。
