Kotani Toshiaki, Nagai Daisuke, Asahi Kensuke, Suzuki Hitomi, Yamao Fumiaki, Kataoka Nobumasa, Yagura Tatsuo
Department of Bioscience, Faculty of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda-shi, Hyogo-ken 669-1337, Japan.
Antimicrob Agents Chemother. 2005 Jul;49(7):2729-34. doi: 10.1128/AAC.49.7.2729-2734.2005.
Bismuth compounds are known for their low levels of toxicity in mammals, and various types of bismuth salts have been used to treat medical disorders. As part of our program to probe this aspect of bismuth chemistry, cyclic organobismuth compounds 1 to 8 bearing a nitrogen or sulfur atom as an additional ring member have been synthesized, and their antimicrobial activities against five standard strains of gram-negative and gram-positive bacteria were assessed. The eight-membered-ring compounds, compounds 1 to 3, exhibited MICs of less than 0.5 microg/ml against Staphylococcus aureus and were more active than the six-membered ones, compounds 5 to 8 (MICs, 4.0 to 16 microg/ml). The gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis, and Enterococcus faecalis) were more susceptible to both types of ring compounds than the gram-negative ones (Escherichia coli and Pseudomonas aeruginosa). Treatment with polymyxin B nonapeptide increased the susceptibility of E. coli to cyclic organobismuth compounds, indicating the low permeability of the outer membrane of gram-negative bacteria to the compounds. Compound 1 also had activity against methicillin-resistant S. aureus, which had an MIC for 90% of the hospital stock strains of 1.25 microg/ml. The killing curves for S. aureus treated with compound 1 or 3 revealed a static effect at a low dose (2x the MIC). However, when S. aureus was treated with 10x the MIC of compound 1 or 3, there was an approximately 3-log reduction in the viable cell number after 48 h of treatment. Electron microscopic inspection demonstrated a considerable increase in the size of S. aureus and the proportion of cells undergoing cell division after treatment with compound 1 at 0.5x the MIC.
铋化合物因其在哺乳动物体内的低毒性而闻名，并且各种铋盐已被用于治疗医学疾病。作为我们探索铋化学这一方面的计划的一部分，已合成了带有氮或硫原子作为额外环成员的环状有机铋化合物1至8，并评估了它们对五种革兰氏阴性和革兰氏阳性细菌标准菌株的抗菌活性。八元环化合物，即化合物1至3，对金黄色葡萄球菌的最低抑菌浓度（MIC）小于0.5微克/毫升，并且比六元环化合物，即化合物5至8（MIC为4.0至16微克/毫升）更具活性。革兰氏阳性细菌（金黄色葡萄球菌、枯草芽孢杆菌和粪肠球菌）比革兰氏阴性细菌（大肠杆菌和铜绿假单胞菌）对这两种环化合物更敏感。用多粘菌素B九肽处理可增加大肠杆菌对环状有机铋化合物的敏感性，这表明革兰氏阴性细菌外膜对这些化合物的通透性较低。化合物1对耐甲氧西林金黄色葡萄球菌也有活性，其对90%的医院库存菌株的MIC为1.25微克/毫升。用化合物1或3处理金黄色葡萄球菌的杀菌曲线显示在低剂量（2倍MIC）时有抑菌作用。然而，当用10倍MIC的化合物1或3处理金黄色葡萄球菌时，处理48小时后活细胞数大约减少3个对数级。电子显微镜检查表明，用0.5倍MIC的化合物1处理后，金黄色葡萄球菌的大小显著增加，且进行细胞分裂的细胞比例增加。
