Division of Infectious Diseases and Geographic Medicine, Dept. of Medicine, Stanford University School of Medicine, Beckman Center, 279 Campus Drive, Stanford, CA 94305, USA.
Department of Chemical Engineering, Stanford University, Stanford, CA, 94305, USA.
Sci Adv. 2024 May 31;10(22):eadl5576. doi: 10.1126/sciadv.adl5576.
Despite great progress in the field, chronic () infections remain a major cause of mortality in patients with cystic fibrosis (pwCF), necessitating treatment with antibiotics. Pf is a filamentous bacteriophage produced by and acts as a structural element in biofilms. Pf presence has been associated with antibiotic resistance and poor outcomes in pwCF, although the underlying mechanisms are unclear. We have investigated how Pf and sputum biopolymers impede antibiotic diffusion using pwCF sputum and fluorescent recovery after photobleaching. We demonstrate that tobramycin interacts with Pf and sputum polymers through electrostatic interactions. We also developed a set of mathematical models to analyze the complex observations. Our analysis suggests that Pf in sputum reduces the diffusion of charged antibiotics due to a greater binding constant associated with organized liquid crystalline structures formed between Pf and sputum polymers. This study provides insights into antibiotic tolerance mechanisms in chronic infections and may offer potential strategies for novel therapeutic approaches.
尽管在该领域取得了巨大进展，但慢性（）感染仍是囊性纤维化（pwCF）患者死亡的主要原因，需要使用抗生素进行治疗。Pf 是一种丝状噬菌体，由（）产生，在生物膜中充当结构元素。尽管潜在机制尚不清楚，但 Pf 的存在与 pwCF 中的抗生素耐药性和不良预后相关。我们已经使用 pwCF 痰液和光漂白后荧光恢复研究了 Pf 和痰液生物聚合物如何阻碍抗生素扩散。我们证明妥布霉素通过静电相互作用与 Pf 和痰液聚合物相互作用。我们还开发了一组数学模型来分析复杂的观察结果。我们的分析表明，由于 Pf 与痰液聚合物之间形成的有组织的液晶结构相关的结合常数更大，因此痰液中的 Pf 会降低带电荷抗生素的扩散。这项研究提供了对慢性（）感染中抗生素耐受机制的深入了解，并可能为新型治疗方法提供潜在策略。
