Cheung K S, Wasserman S A, Dudek E, Lerner S A, Johnston M
J Med Chem. 1983 Dec;26(12):1733-41. doi: 10.1021/jm00366a015.
A set of dipeptides containing the amino acid residues beta-chloroalanine and propargylglycine, which are mechanism-based inactivators of purified microbial enzymes (alanine racemase and cystathionine gamma-synthase, respectively), have been synthesized, and their antibacterial properties in vitro have been evaluated. Dipeptides containing a single beta-chloro-L-alanyl residue (e.g., 3, 5, 9, and 10) or a single L-propargylglycyl residue (e.g., 12 and 15) are potent antibacterials. The in vitro antibiotic activity of beta-chloro-L-alanine and of L-propargylglycine is increased as much as 4000-fold by incorporation of these residues into a dipeptide. Compounds that contain only a single enzyme-inactivating amino acid together with a second L-alanyl residue (3, 5, 12, and 15) have a restricted range of activity: of the species tested, only Streptococcus agalactiae, Staphylococcus aureus, and Staphylococcus epidermidis are sensitive. However, peptides that contain two suicide-substrate residues [e.g., beta-Cl-LAla-beta-Cl-LAla (8) or LppGly-LppGly (18)] are broad-spectrum antibacterials; as many as 12 different species of the 16 surveyed are sensitive. Dipeptides that contain an amino-terminal L-methionyl (9) or an L-norvalyl (10) residue and a carboxy-terminal beta-chloro-L-alanyl unit are also effective against a large number of organisms; the spectra of activity are like those seen for 8 and 18. A "mixed" dipeptide [beta-Cl-LAla-LppGly, (21)] gives apparent synergism of antibiotic action of beta-chloro-L-alanine and of L-propargylglycine when these two residues are incorporated into a single structure. Peptides of the D,D configuration (4, 6, 13, 16, and 20) and ones of L,D stereochemistry (e.g., 7) are not antibacterials. Peptides containing one (11 and 14) and two (17) D,L-propargylglycyl residues are unresolved sets of diastereomers; the mixtures of compounds are between two- and fourfold less active than the correspondingly resolved L,L dipeptides (12, 15, and 18). These findings are consistent with a mechanism of action for these antibiotics involving stereoselective processing of the peptidyl unit in vivo.
已合成了一组含有β-氯丙氨酸和炔丙基甘氨酸氨基酸残基的二肽，它们分别是纯化的微生物酶（丙氨酸消旋酶和胱硫醚γ-合酶）的基于机制的失活剂，并评估了它们的体外抗菌特性。含有单个β-氯-L-丙氨酰残基（例如3、5、9和10）或单个L-炔丙基甘氨酰残基（例如12和15）的二肽是强效抗菌剂。通过将这些残基掺入二肽中，β-氯-L-丙氨酸和L-炔丙基甘氨酸的体外抗生素活性提高了多达4000倍。仅含有单个酶失活氨基酸与第二个L-丙氨酰残基（3、5、12和15）的化合物具有有限的活性范围：在所测试的物种中，只有无乳链球菌、金黄色葡萄球菌和表皮葡萄球菌敏感。然而，含有两个自杀底物残基[例如β-Cl-LAla-β-Cl-LAla（8）或LppGly-LppGly（18）]的肽是广谱抗菌剂；在调查的16个物种中，多达12个不同物种敏感。含有氨基末端L-甲硫氨酰（9）或L-正缬氨酰（10）残基和羧基末端β-氯-L-丙氨酰单元的二肽也对大量生物体有效；活性谱与8和18的相似。当这两个残基掺入单个结构中时，“混合”二肽[β-Cl-LAla-LppGly，（21）]显示出β-氯-L-丙氨酸和L-炔丙基甘氨酸抗生素作用的明显协同作用。D，D构型（4、6、13、16和20）的肽和L，D立体化学的肽（例如7）不是抗菌剂。含有一个（11和14）和两个（17）D，L-炔丙基甘氨酰残基的肽是未解析的非对映异构体组；化合物混合物的活性比相应解析的L，L二肽（12、15和18）低两到四倍。这些发现与这些抗生素的作用机制一致，该机制涉及体内肽基单元的立体选择性加工。
