Domenico P, Salo R J, Novick S G, Schoch P E, Van Horn K, Cunha B A
Infectious Disease Division, Winthrop-Unversity Hospital, Mineola, New York 11501, USA.
Antimicrob Agents Chemother. 1997 Aug;41(8):1697-703. doi: 10.1128/AAC.41.8.1697.
The antibacterial properties of bismuth are greatly enhanced when bismuth is combined with certain lipophilic thiol compounds. Antibacterial activity was enhanced from 25- to 300-fold by the following seven different thiols, in order of decreasing synergy: 1,3-propanedithiol, dimercaprol (BAL), dithiothreitol, 3-mercapto-2-butanol, beta-mercaptoethanol, 1-monothioglycerol, and mercaptoethylamine. The dithiols produced the greatest synergy with bismuth at optimum bismuth-thiol molar ratios of from 3:1 to 1:1. The monothiols were generally not as synergistic and required molar ratios of from 1:1 to 1:4 for optimum antibacterial activity. The most-active mono- or dithiols were also the most soluble in butanol. The intensity of the yellow formed by bismuth-thiol complexes reflected the degree of chelation and correlated with antibacterial potency at high molar ratios. The bismuth-BAL compound (BisBAL) was active against most bacteria, as assessed by broth dilution, agar diffusion, and agar dilution analyses. Staphylococci (MIC, 5 to 7 microM Bi3+) and Helicobacter pylori (MIC, 2.2 microM) were among the most sensitive bacteria. Gram-negative bacteria were sensitive (MIC, < 17 microM). Enterococci were relatively resistant (MIC, 63 microM Bi3+). The MIC range for anaerobes was 15 to 100 microM Bi3+, except for Clostridium difficile (MIC, 7.5 microM). Bactericidal activity averaged 29% above the MIC. Bactericidal activity increased with increasing pH and/or increasing temperature. Bismuth-thiol solubility, stability, and antibacterial activity depended on pH and the bismuth-thiol molar ratio. BisBAL was stable but ineffective against Escherichia coli at pH 4. Activity and instability (reactivity) increased with increasing alkalinity. BisBAL was acid soluble at a molar ratio of greater than 3:2 and alkaline soluble at a molar ratio of less than 2:3. In conclusion, certain lipophilic thiol compounds enhanced bismuth antibacterial activity against a broad spectrum of bacteria. The activity, solubility, and stability of BisBAL were strongly dependent on the pH, temperature, and molar ratio. Chelation of bismuth with certain thiol agents enhanced the solubility and lipophilicity of this cationic heavy metal, thereby significantly enhancing its potency and versatility as an antibacterial agent.
铋与某些亲脂性硫醇化合物结合时，其抗菌性能会大大增强。以下七种不同的硫醇按协同作用递减顺序排列，可使抗菌活性提高25至300倍：1,3 - 丙二硫醇、二巯丙醇（BAL）、二硫苏糖醇、3 - 巯基 - 2 - 丁醇、β - 巯基乙醇、1 - 单硫甘油和巯基乙胺。在铋与硫醇的最佳摩尔比为3:1至1:1时，二硫醇与铋产生的协同作用最大。单硫醇的协同作用通常较弱，最佳抗菌活性需要的摩尔比为1:1至1:4。活性最高的单硫醇或二硫醇在丁醇中的溶解度也最高。铋 - 硫醇络合物形成的黄色强度反映了螯合程度，并与高摩尔比下的抗菌效力相关。通过肉汤稀释、琼脂扩散和琼脂稀释分析评估，铋 - BAL化合物（BisBAL）对大多数细菌具有活性。葡萄球菌（MIC，5至7 microM Bi3 +）和幽门螺杆菌（MIC，2.2 microM）是最敏感的细菌之一。革兰氏阴性菌敏感（MIC，<17 microM）。肠球菌相对耐药（MIC，63 microM Bi3 +）。厌氧菌的MIC范围为15至100 microM Bi3 +，艰难梭菌除外（MIC，7.5 microM）。杀菌活性平均比MIC高29%。杀菌活性随pH值升高和/或温度升高而增加。铋 - 硫醇的溶解度、稳定性和抗菌活性取决于pH值和铋 - 硫醇的摩尔比。BisBAL在pH 4时对大肠杆菌稳定但无效。随着碱性增强，活性和不稳定性（反应性）增加。BisBAL在摩尔比大于3:2时可酸溶，在摩尔比小于2:3时可碱溶。总之，某些亲脂性硫醇化合物可增强铋对多种细菌的抗菌活性。BisBAL的活性、溶解度和稳定性强烈依赖于pH值、温度和摩尔比。铋与某些硫醇试剂的螯合增强了这种阳离子重金属的溶解度和亲脂性，从而显著提高了其作为抗菌剂的效力和通用性。
