Abstract：
Antimicrobial resistance is becoming more prominent day after day due to a number of mechanisms by microbes, especially the sophisticated biological barriers of bacteria, especially in Gram-negatives. There, the lipopolysaccharides (LPS) layer is a unique component of the outer leaflet of the outer membrane which is highly impermeable and prevents antibiotics from passing passively into the intracellular compartments. Biodynamers, a novel class of dynamically bio-responsive polymers, may open new perspectives to overcome this particular barrier by accommodating various secondary structures and form supramolecular structures in such bacterial microenvironments. Generally, bio-responsive polymers are not only candidates as bio-active molecules against bacteria but also carriers via their interactions with the cargo. Based on their dynamicity, design flexibility, biodegradability, biocompatibility, and pH-responsiveness, we investigated the potential of two peptide-based biodynamers for improving antimicrobial drug delivery. By a range of experimental methods, we discovered a greater affinity of Arg-biodynamers for bacterial membranes than for mammalian membranes as well as an enhanced LPS targeting on the bacterial membrane, opening perspectives for enhancing the delivery of antimicrobials across the Gram-negative bacterial cell envelope. This could be explained by the change of the secondary structure of Arg-biodynamers into a predominant β-sheet character in the LPS microenvironment, by contrast to the α-helical structure typically observed for most lipid membrane-permeabilizing peptides. In comparison to poly-L-arginine, the intrinsic antibacterial activity of Arg-biodynamers was nearly unchanged, but its toxicity against mammalian cells was >128-fold reduced. When used in bacterio as an antibiotic potentiator, however, Arg-biodynamers improved the minimum inhibitory concentration (MIC) against Escherichia coli by 32 times compared to colistin alone. Similar effect has also been observed in two stains of Pseudomonas aeruginosa. Arg-biodynamers may therefore represent an interesting option as an adjuvant for antibiotics against Gram-negative bacteria and to overcome antimicrobial resistance.
摘要：
由于微生物的多种机制，抗菌素耐药性日复一日变得越来越突出，尤其是细菌的复杂生物屏障，尤其是革兰氏阴性。在那里,脂多糖(LPS)层是外膜的外小叶的独特组分,其是高度不可渗透的并且防止抗生素被动地进入细胞内区室。生物动力学,一类新型的动态生物响应聚合物，可以通过容纳各种二级结构并在此类细菌微环境中形成超分子结构来打开新的观点来克服这种特定的障碍。一般来说,生物响应性聚合物不仅是针对细菌的生物活性分子，而且是通过与货物相互作用的载体。辛格等人。(2019)[1]基于它们的动态性，设计的灵活性，生物降解性，生物相容性，和pH响应性，我们研究了两种基于肽的生物动力学改善抗菌药物递送的潜力.通过一系列实验方法，我们发现，与哺乳动物膜相比，Arg生物动力学对细菌膜具有更大的亲和力，并且增强了LPS对细菌膜的靶向作用，开放的观点，以增强跨革兰氏阴性细菌细胞包膜的抗微生物剂的递送。这可以通过在LPS微环境中Arg生物动力学的二级结构变为主要的β折叠特性来解释。与大多数脂质膜透化肽通常观察到的α-螺旋结构相反。与聚-L-精氨酸相比,精氨酸生物动力学的内在抗菌活性几乎没有变化，但其对哺乳动物细胞的毒性降低了128倍。当在细菌中用作抗生素增效剂时，然而,与单独的粘菌素相比，Arg生物动力学对大肠杆菌的最低抑菌浓度（MIC）提高了32倍。在铜绿假单胞菌的两种染色中也观察到类似的效果。因此，Arg生物动力学可能是一种有趣的选择，可作为抗生素对革兰氏阴性菌的佐剂，并克服抗微生物耐药性。
