Synthetic Immunotherapeutics against Gram-negative Pathogens,Cell Chemical Biology

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Synthetic Immunotherapeutics against Gram-negative Pathogens
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2018-07-05 , DOI: 10.1016/j.chembiol.2018.05.019
Mary Sabulski Feigman ₁ , Seonghoon Kim ₂ , Sean E Pidgeon ₁ , Yuming Yu ₁ , George Mogambi Ongwae ₁ , Dhilon S Patel ₂ , Steven Regen ₁ , Wonpil Im ₂ , Marcos M Pires ₁

Affiliation

While traditional drug discovery continues to be an important platform for the search of new antibiotics, alternative approaches should also be pursued to complement these efforts. We herein designed a class of molecules that decorate bacterial cell surfaces with the goal of re-engaging components of the immune system towardEscherichia coliandPseudomonas aeruginosa. More specifically, conjugates were assembled using polymyxin B (an antibiotic that inherently attaches to the surface of Gram-negative pathogens) and antigenic epitopes that recruit antibodies found in human serum. We established that the spacer length played a significant role in hapten display within the bacterial cell surface, a result that was confirmed both experimentally and via molecular dynamics simulations. Most importantly, we demonstrated the specific killing of bacteria by our agent in the presence of human serum. By enlisting the immune system, these agents have the potential to pave the way for a potent antimicrobial modality.

中文翻译：

针对革兰氏阴性病原体的合成免疫疗法

虽然传统药物发现仍然是寻找新抗生素的重要平台，但也应该寻求替代方法来补充这些努力。我们在此设计了一类装饰细菌细胞表面的分子，目的是使免疫系统的成分重新与大肠杆菌和铜绿假单胞菌结合。更具体地说，使用多粘菌素 B（一种固有地附着在革兰氏阴性病原体表面的抗生素）和招募人血清中发现的抗体的抗原表位组装缀合物。我们确定间隔区长度在细菌细胞表面内的半抗原展示中发挥重要作用，这一结果已通过实验和分子动力学模拟得到证实。最重要的是，我们证明了我们的试剂在人血清存在的情况下可以特异性杀死细菌。通过调动免疫系统，这些药物有可能为有效的抗菌方式铺平道路。

更新日期：2018-10-19

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