Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio, USA.
Antimicrob Agents Chemother. 2022 Mar 15;66(3):e0187721. doi: 10.1128/AAC.01877-21. Epub 2022 Jan 10.
New strategies to treat diseases in which biofilms contribute significantly to pathogenesis are needed, as biofilm-resident bacteria are highly recalcitrant to antibiotics due to physical biofilm architecture and a canonically quiescent metabolism, among many additional attributes. We, and others, have shown that when biofilms are dispersed or disrupted, bacteria released from biofilm residence are in a distinct physiologic state that, in part, renders these bacteria highly sensitive to killing by specific antibiotics. We sought to demonstrate the breadth of the ability of a recently humanized monoclonal antibody against an essential biofilm structural element (DNABII protein) to disrupt biofilms formed by respiratory tract pathogens and potentiate antibiotic-mediated killing of bacteria released from biofilm residence. Biofilms formed by six respiratory tract pathogens were significantly disrupted by the humanized monoclonal antibody in a dose- and time-dependent manner, as corroborated by confocal laser scanning microscopy (CLSM) imaging. Bacteria newly released from the biofilms of 3 of 6 species were significantly more sensitive than their planktonic counterparts to killing by 2 of 3 antibiotics currently used clinically and were now also equally as sensitive to killing by the 3rd antibiotic. The remaining 3 pathogens were significantly more susceptible to killing by all 3 antibiotics. A humanized monoclonal antibody directed against protective epitopes of a DNABII protein effectively released six diverse respiratory tract pathogens from biofilm residence in a phenotypic state that was now as, or significantly more, sensitive to killing by three antibiotics currently indicated for use clinically. These data support this targeted, combinatorial, species-agnostic therapy to mitigate chronic bacterial diseases.
需要新的策略来治疗那些生物膜对发病机制有重大贡献的疾病，因为生物膜内的细菌由于物理生物膜结构和典型的休眠代谢等多种特性，对抗生素具有很强的抗性。我们和其他人已经表明，当生物膜被分散或破坏时，从生物膜中释放出来的细菌处于一种独特的生理状态，部分原因是这些细菌对特定抗生素的杀伤高度敏感。我们试图证明一种针对重要生物膜结构元素（DNABII 蛋白）的人源化单克隆抗体的广泛能力，该抗体可以破坏呼吸道病原体形成的生物膜，并增强抗生素介导的从生物膜中释放的细菌的杀伤作用。六种呼吸道病原体形成的生物膜在剂量和时间依赖性方式下，均被人源化单克隆抗体显著破坏，共聚焦激光扫描显微镜（CLSM）成像也证实了这一点。从 6 种生物膜中的 3 种新释放的细菌比其浮游菌对 2 种目前临床上使用的抗生素的杀伤作用更为敏感，而且现在对第 3 种抗生素的杀伤作用也同样敏感。其余 3 种病原体对所有 3 种抗生素的杀伤作用明显增强。针对 DNABII 蛋白保护性表位的人源化单克隆抗体有效地将六种不同的呼吸道病原体从生物膜中释放出来，使其处于一种表型状态，对三种目前临床上推荐使用的抗生素的杀伤作用更为敏感。这些数据支持这种针对特定目标、组合、无种属限制的治疗方法，以减轻慢性细菌性疾病。
