Yeh Shang-Lin, Narasimhalu Naveen, Vom Steeg Landon G, Muthami Joy, LeConey Sean, He Zeming, Pitcher Mica, Cassady Harrison, Morley Valerie J, Cho Sung Hyun, Bator Carol, Koshani Roya, Woods Robert J, Hickner Michael, Read Andrew F, Sheikhi Amir
Department of Chemical Engineering, The Pennsylvania State University, University Park, Pennsylvania 16802, United States.
Department of Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, United States.
ACS Appl Mater Interfaces. 2022 Sep 28;14(38):42864-42875. doi: 10.1021/acsami.2c14894. Epub 2022 Sep 14.
Daptomycin (DAP), a cyclic anionic lipopeptide antibiotic, is among the last resorts to treat multidrug-resistant Gram-positive bacterial infections, caused by vancomycin-resistant or methicillin-resistant . DAP is administered intravenously, and via biliary excretion, ∼5-10% of the intravenous DAP dose arrives in the gastrointestinal (GI) tract where it drives resistance evolution in the off-target populations of bacteria. Previously, we have shown that the oral administration of cholestyramine, an ion exchange biomaterial (IXB) sorbent, prevents DAP treatment from enriching DAP resistance in the populations of shed from mice. Here, we investigate the biomaterial-DAP interfacial interactions to uncover the antibiotic removal mechanisms. The IXB-mediated DAP capture from aqueous media was measured in controlled pH/electrolyte solutions and in the simulated intestinal fluid (SIF) to uncover the molecular and colloidal mechanisms of DAP removal from the GI tract. Our findings show that the IXB electrostatically adsorbs the anionic antibiotic via a time-dependent diffusion-controlled process. Unsteady-state diffusion-adsorption mass balance describes the dynamics of adsorption well, and the maximum removal capacity is beyond the electric charge stoichiometric ratio because of DAP self-assembly. This study may open new opportunities for optimizing cholestyramine adjuvant therapy to prevent DAP resistance, as well as designing novel biomaterials to remove off-target antibiotics from the GI tract.
达托霉素（DAP）是一种环状阴离子脂肽抗生素，是治疗由耐万古霉素或耐甲氧西林引起的多重耐药革兰氏阳性菌感染的最后手段之一。DAP通过静脉给药，经胆汁排泄，静脉注射剂量的约5-10%会到达胃肠道（GI），在那里它会促使肠道细菌的非靶标菌群产生耐药性进化。此前，我们已经表明，口服离子交换生物材料（IXB）吸附剂消胆胺可防止DAP治疗使从小鼠体内排出的细菌群体中富集DAP耐药性。在此，我们研究生物材料与DAP的界面相互作用，以揭示抗生素清除机制。在受控的pH/电解质溶液和模拟肠液（SIF）中测量了IXB介导的从水介质中捕获DAP的情况，以揭示从胃肠道清除DAP的分子和胶体机制。我们的研究结果表明，IXB通过时间依赖性扩散控制过程静电吸附阴离子抗生素。非稳态扩散-吸附质量平衡很好地描述了吸附动力学，并且由于DAP的自组装，最大去除能力超出了电荷化学计量比。这项研究可能为优化消胆胺辅助治疗以预防DAP耐药性，以及设计新型生物材料以从胃肠道中去除非靶标抗生素开辟新的机会。
