完美的青霉素？肽聚糖模拟β-内酰胺对细菌DD-肽酶的抑制作用
The perfect penicillin? Inhibition of a bacterial DD-peptidase by peptidoglycan-mimetic beta-lactams.
作者信息
Josephine Helen R, Kumar Ish, Pratt R F
机构信息
Department of Chemistry, Wesleyan University, Lawn Avenue, Middletown, CT 06459, USA.
出版信息
J Am Chem Soc. 2004 Jul 7;126(26):8122-3. doi: 10.1021/ja048850s.
6-(Glycyl-l-alpha-aminopimelyl)-aminopenicillanic acid and 7-(glycyl-l-alpha-aminopimelyl)-aminocephalosporanic acid have been synthesized as Streptomyces sp. peptidoglycan-mimetic beta-lactams. These compounds inactivate the Streptomyces R61 DD-peptidase with rate constants of 1.5 x 107 s-1 M-1 and 5.6 x 105 s-1 M-1, respectively. The former compound is thus the most effective beta-lactam inhibitor of a DD-peptidase yet described. The analogous d-alanyl-d-alanine peptide has previously been shown to react with this enzyme with comparable efficiency, kcat/Km = 8.7 x 106 s-1 M-1. These results show that, in this case at least, incorporation of a peptidoglycan-mimetic side chain into a beta-lactam greatly enhances its activity as a DD-peptidase inhibitor. This result has interesting implications for beta-lactam design.
6-（甘氨酰-L-α-氨基庚二酰）-氨基青霉烷酸和7-（甘氨酰-L-α-氨基庚二酰）-氨基头孢烷酸已被合成为链霉菌属的肽聚糖模拟β-内酰胺。这些化合物使链霉菌R61的DD-肽酶失活，速率常数分别为1.5×10⁷ s⁻¹ M⁻¹和5.6×10⁵ s⁻¹ M⁻¹。因此，前一种化合物是迄今所描述的最有效的DD-肽酶β-内酰胺抑制剂。类似的D-丙氨酰-D-丙氨酸肽先前已被证明能以相当的效率与该酶反应，kcat/Km = 8.7×10⁶ s⁻¹ M⁻¹。这些结果表明，至少在这种情况下，将肽聚糖模拟侧链引入β-内酰胺可大大增强其作为DD-肽酶抑制剂的活性。这一结果对β-内酰胺设计具有有趣的启示。
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