Department of Chemistry, Merkert Chemistry Center , Boston College , Chestnut Hill , Massachusetts 02467 , United States.
Department of Biology , Boston College , Chestnut Hill , Massachusetts 02467 , United States.
J Am Chem Soc. 2018 May 16;140(19):6137-6145. doi: 10.1021/jacs.8b02461. Epub 2018 May 3.
Antibiotic resistance of bacterial pathogens poses an increasing threat to the wellbeing of our society and urgently calls for new strategies for infection diagnosis and antibiotic discovery. The antibiotic resistance problem at least partially arises from extensive use of broad-spectrum antibiotics. Ideally, for the treatment of infection, one would like to use a narrow-spectrum antibiotic that specifically targets and kills the disease-causing strain. This is particularly important considering the commensal bacterial species that are beneficial and sometimes even critical to the health of a human being. In this contribution, we describe a phage display platform that enables rapid identification of peptide probes for specific bacterial strains. The phage library described herein incorporates 2-acetylphenylboronic acid moieties to elicit dynamic covalent binding to the bacterial cell surface. Screening of the library against live bacterial cells yields submicromolar and highly specific binders for clinical strains of Staphylococcus aureus and Acinetobacter baumannii that display antibiotic resistance. We further show that the identified peptide probes can be readily converted to bactericidal agents that deliver generic toxins to kill the targeted bacterial strain with high specificity. The phage display platform described here is applicable to a wide array of bacterial strains, paving the way to facile diagnosis and development of strain-specific antibiotics.
细菌病原体的抗生素耐药性对我们社会的健康构成了日益严重的威胁，迫切需要新的感染诊断和抗生素发现策略。抗生素耐药性问题至少部分源于广谱抗生素的广泛使用。理想情况下，为了治疗感染，人们希望使用一种专门针对并杀死致病菌株的窄谱抗生素。考虑到对人类健康有益甚至至关重要的共生细菌种类，这一点尤为重要。在本研究中，我们描述了一种噬菌体展示平台，该平台可用于快速鉴定针对特定细菌菌株的肽探针。本文所述的噬菌体文库包含 2-乙酰苯硼酸部分，以引起与细菌表面的动态共价结合。对文库进行活细菌细胞筛选，可获得针对耐抗生素的金黄色葡萄球菌和鲍曼不动杆菌临床菌株的亚毫摩尔和高度特异性结合物。我们进一步表明，鉴定出的肽探针可以很容易地转化为杀菌剂，将通用毒素递送至靶细菌菌株，具有很高的特异性。这里描述的噬菌体展示平台适用于广泛的细菌菌株，为简便诊断和开发针对菌株的抗生素铺平了道路。
