Mengelers M J, Hougee P E, Janssen L H, Van Miert A S
State Institute for Quality Control of Agricultural Products (RIKILT-DLO), Department of Risk Assessment & Toxicology, Wageningen, The Netherlands.
J Vet Pharmacol Ther. 1997 Aug;20(4):276-83. doi: 10.1046/j.1365-2885.1997.00063.x.
Relationships between the antimicrobial activities of sulfonamides and physicochemical properties including the acid dissociation constant (pKa) and the hydrophobicity constant (pi) were determined. The minimal inhibitory concentrations (MIC) of sulfonamides against Actinobacillus pleuropneumoniae, a gram-negative veterinary pathogen, were used. High performance liquid chromatography was applied for the determination of the electronic and hydrophobic parameters. Empirically determined relationships pointed out the dominant role of the degree of ionization on the antimicrobial activity. The data indicate that hydrophobic properties of sulfonamides, characterized by pi, are of minor importance for the in vitro antibacterial activity. Because of the restricted pKa range (4.9-7.7) it could not be established whether the relationship between pKa and activity was linear or bilinear. Whenever o,m-disubstituted sulfonamides were included correlations decreased substantially. Relationships based on multicompartment equilibrium models were derived and indicated a bilinear relation between pKa and MIC. Model-based equations showed that the antibacterial activity was governed by the extracellular ionic concentration of the sulfonamides whenever different intra and extracellular pH values were assumed in the equilibrium model. The antimicrobial activities of the sulfonamides against gram-positive organisms were also related to the degree of ionization of the sulfonamides in the agar medium.
测定了磺胺类药物的抗菌活性与包括酸解离常数（pKa）和疏水性常数（π）在内的物理化学性质之间的关系。使用了磺胺类药物对革兰氏阴性兽医病原体胸膜肺炎放线杆菌的最低抑菌浓度（MIC）。采用高效液相色谱法测定电子和疏水参数。根据经验确定的关系指出了电离程度对抗菌活性的主导作用。数据表明，以π表征的磺胺类药物的疏水性质对体外抗菌活性的重要性较小。由于pKa范围有限（4.9 - 7.7），无法确定pKa与活性之间的关系是线性还是双线性。每当包含邻、间二取代磺胺类药物时，相关性会大幅下降。推导了基于多室平衡模型的关系，并表明pKa与MIC之间存在双线性关系。基于模型的方程表明，当在平衡模型中假设细胞内和细胞外pH值不同时，磺胺类药物的抗菌活性受其细胞外离子浓度的控制。磺胺类药物对革兰氏阳性菌的抗菌活性也与琼脂培养基中磺胺类药物的电离程度有关。
