A High-Affinity Native Human Antibody Disrupts Biofilm from Staphylococcus aureus Bacteria and Potentiates Antibiotic Efficacy in a Mouse Implant Infection Model
A High-Affinity Native Human Antibody Disrupts Biofilm from Staphylococcus aureus Bacteria and Potentiates Antibiotic Efficacy in a Mouse Implant Infection Model
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DOI：
10.1128/aac.02588-15
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发表时间：
2016-04-01
影响因子：
4.9
通讯作者：
Kauvar, Lawrence M.
中科院分区：
文献类型：
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作者：
Estelles, Angeles;Woischnig, Anne-Kathrin;Kauvar, Lawrence M.
许多严重的细菌感染由于生物膜形成而难以治疗，生物膜形成提供了物理保护并诱导了与无菌状态相比对抗生素治疗难治的固着表型。生物膜的关键结构组分是细胞外DNA，其由来自DNABII家族的分泌的细菌蛋白保持在适当位置：整合宿主因子（IHF）和组蛋白样（HU）蛋白。使用单B淋巴细胞筛选技术发现了天然人单克隆抗体TRL 1068。它对来自重要革兰氏阳性和革兰氏阴性细菌病原体的DNABII同源物具有低皮摩尔亲和力。在1.2 μ g/ml的抗体浓度下，在体外观察到12小时内建立的生物膜的破坏。在鼠组织笼感染模型中评价TRL 1068的体内作用，其中通过用耐甲氧西林金黄色葡萄球菌（MRSA; ATCC 43300）感染形成生物膜。通过TRL 1068（15 mg/kg体重，腹膜内[i. p.]给药）与达托霉素（50 mg/kg，i. p.）与单独的达托霉素处理后相比，粘附细菌计数显著降低，同时粘附细菌数量显著降低。样品基质中TRL 1068的定量显示TRL 1068从血清中大量渗透到笼内部。TRL 1068是与标准护理抗生素联合治疗的临床候选药物，以克服与生物膜形成相关的药物难治性状态，具有广泛的难治性细菌感染的潜在效用。
Many serious bacterial infections are difficult to treat due to biofilm formation, which provides physical protection and induces a sessile phenotype refractory to antibiotic treatment compared to the planktonic state. A key structural component of biofilm is extracellular DNA, which is held in place by secreted bacterial proteins from the DNABII family: integration host factor (IHF) and histone-like (HU) proteins. A native human monoclonal antibody, TRL1068, has been discovered using single B-lymphocyte screening technology. It has low-picomolar affinity against DNABII homologs from important Gram-positive and Gram-negative bacterial pathogens. The disruption of established biofilm was observed in vitro at an antibody concentration of 1.2 mu g/ml over 12 h. The effect of TRL1068 in vivo was evaluated in a murine tissue cage infection model in which a biofilm is formed by infection with methicillin-resistant Staphylococcus aureus (MRSA; ATCC 43300). Treatment of the established biofilm by combination therapy of TRL1068 (15 mg/kg of body weight, intraperitoneal [i.p.] administration) with daptomycin (50 mg/kg, i.p.) significantly reduced adherent bacterial count compared to that after daptomycin treatment alone, accompanied by significant reduction in planktonic bacterial numbers. The quantification of TRL1068 in sample matrices showed substantial penetration of TRL1068 from serum into the cage interior. TRL1068 is a clinical candidate for combination treatment with standard-of-care antibiotics to overcome the drug-refractory state associated with biofilm formation, with potential utility for a broad spectrum of difficult-to-treat bacterial infections.