The role of hydrophobic side chains as determinants of antibacterial activity of semisynthetic glycopeptide antibiotics
The role of hydrophobic side chains as determinants of antibacterial activity of semisynthetic glycopeptide antibiotics
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DOI：
10.7164/antibiotics.50.677
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发表时间：
1997-08-01
影响因子：
3.3
通讯作者：
Hobbs, JN
中科院分区：
文献类型：
--
作者：
Allen, NE;LeTourneau, DL;Hobbs, JN
检查万古霉素、LY 264826和LY 264826的四种N-取代衍生物的二聚化、与含有D-丙氨酰-D-丙氨酸和D-丙氨酰-D-乳酸的细胞壁配体的结合以及与细菌膜囊泡的结合。这六种糖肽类抗生素对藤黄微球菌的抗菌活性范围为360倍（MIC = 0.00072类似于0.26 μ M），N-取代的化合物具有最低的MIC。万古霉素、LY 264826和四种N-取代的衍生物对N，N '-二乙酰基-L-赖氨酰-D-丙氨酰-D-丙氨酸（K-b = 1.5 x 10（5），类似于5.9 x 10（5）M-1）。结合N，N '-二乙酰基-L-赖氨酰-D-丙氨酰-D-乳酸的亲和力较低，但也代表了较窄的范围（K-b = 0.24 x 10（3），类似于1.6 x 10（3）M-1）。与配体结合相反，六种化合物二聚化的相对能力相差四个数量级（K-dim = 4.9 x 10（1），类似于1.2 x 10（6）M-1）。N-取代的衍生物具有最高的k（dim）值，需要最大摩尔过量的外源细胞壁配体来抑制抑制，并表现出结合细菌膜囊泡的倾向。具有最亲脂性侧链的衍生物与囊泡的结合程度最高。研究结果表明，LY 264826的N-取代衍生物的增强的抗菌活性来自疏水侧链的性质，其可以对二聚化和膜结合产生显著影响。
Vancomycin, LY264826 and four N-substituted derivatives of LY264826 were examined for dimerization, binding to D-alanyl-D-alanine-and D-alanyl-D-lactate-containing cell wall ligands, and binding to bacterial membrane vesicles. The six glycopeptide antibiotics represent a 360-fold range in antibacterial activities against Micrococcus luteus (MIC = 0.00072 similar to 0.26 mu M) with the N-substituted compounds having the lowest MICs. Vancomycin, LY264826 and the four N-substituted derivatives shared nearly identical binding affinities for N,N'-diacetyl-L-lysyl-D-alanyl-D-alanine (K-b = 1.5 x 10(5) similar to 5.9 x 10(5) M-1). Affinities for binding N,N'-diacetyl-L-lysyl-D-alanyl-D-lactate were lower but also represented a narrow range (K-b = 0.24 x 10(3) similar to 1.6 x 10(3) M-1). In contrast to ligand binding, the relative capacity of the six compounds to dimerize differed by four orders of magnitude (K-dim = 4.9 x 10(1) similar to 1.2 x 10(6) M-1). The N-substituted derivatives had the highest k(dim) values, required the greatest molar excess of exogenous cell wall ligand to suppress inhibition, and demonstrated a propensity to bind to bacterial membrane vesicles. The derivatives with the most lipophilic side chains were the most highly bound to vesicles. The findings suggest that the enhanced antibacterial activities of N-substituted derivatives of LY264826 derive from the nature of the hydrophobic side chain which can have a marked effect on dimerization and membrane binding.