Dings Ruud P M, Haseman Judith R, Leslie Dan B, Luong Mike, Dunn David L, Mayo Kevin H
Department of Biochemistry, University of Minnesota Health Science Center, Minneapolis, MN 55455, USA.
Biochim Biophys Acta. 2013 Jun;1830(6):3454-7. doi: 10.1016/j.bbagen.2013.02.002. Epub 2013 Feb 9.
Dodecapeptide SC4 is a broad-spectrum bactericidal agent that functions by disintegrating bacterial membranes and neutralizing endotoxins. For insight into which SC4 amino acids are functionally important, we assessed Gram-negative bactericidal effects in structure-activity relationship experiments. Subsequently, SC4 was tested in a murine bacteremia model to combine and compare the efficacy with Zosyn, a first-line antibiotic against Pseudomonas aeruginosa (P. aeruginosa).
SC4 alanine-scanning analogs and their activities on were tested on P. aeruginosa. Survival studies in P. aeruginosa challenged mice were executed to monitor overall efficacy of SC4 and Zosyn, as a single modality and also as combination treatment. ELISAs were used to measure blood serum levels of selected inflammatory cytokines during treatment.
Cationic residues were found to play a crucial role in terms of bactericidal activity against P. aeruginosa. In vivo, while only 9% (3/34) of control animals survived to day two and beyond, 44% (12/27) to 41% (14/34) of animals treated with SC4 or Zosyn, respectively, survived beyond one week. Combination treatment of SC4 and Zosyn demonstrated improved survival, i.e. 60% (12/20). The TNFα, IL-1, and IL-6 serum levels were attenuated in each treatment group compared to the control group.
These data show that combination treatment of SC4 and Zosyn is most effective at killing P. aeruginosa and attenuating inflammatory cytokine levels in vivo.
Combination treatment of SC4 and Zosyn may be useful in the clinic as a more effective antibiotic therapy against Gram-negative infectious diseases.
十二肽SC4是一种广谱杀菌剂，其作用机制是破坏细菌细胞膜并中和内毒素。为了深入了解SC4的哪些氨基酸具有重要功能，我们在构效关系实验中评估了其对革兰氏阴性菌的杀菌作用。随后，在小鼠菌血症模型中对SC4进行了测试，以将其疗效与抗铜绿假单胞菌的一线抗生素舒普深进行联合比较。
测试了SC4丙氨酸扫描类似物及其对铜绿假单胞菌的活性。在感染铜绿假单胞菌的小鼠中进行生存研究，以监测SC4和舒普深作为单一治疗方式以及联合治疗的总体疗效。在治疗期间，使用酶联免疫吸附测定法（ELISA）测量选定炎症细胞因子的血清水平。
发现阳离子残基对铜绿假单胞菌的杀菌活性起着关键作用。在体内，对照组动物中只有9%（3/34）存活至第二天及以后，而分别用SC4或舒普深治疗的动物中有44%（12/27）至41%（14/34）存活超过一周。SC4和舒普深联合治疗显示存活率提高，即60%（12/20）。与对照组相比，每个治疗组的肿瘤坏死因子α（TNFα）、白细胞介素-1（IL-1）和白细胞介素-6（IL-6）血清水平均有所降低。
这些数据表明，SC4和舒普深联合治疗在体内杀灭铜绿假单胞菌和降低炎症细胞因子水平方面最有效。
SC4和舒普深联合治疗作为一种更有效的抗革兰氏阴性传染病的抗生素疗法，可能在临床上有用。
