Biofilm infections between Scylla and Charybdis: interplay of host antimicrobial peptides and antibiotics.
Biofilm infections between Scylla and Charybdis: interplay of host antimicrobial peptides and antibiotics.
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DOI：
10.2147/idr.s157847
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发表时间：
2018
影响因子：
3.9
通讯作者：
Yakovlev A
中科院分区：
文献类型：
--
作者：
Chernysh S;Gordya N;Tulin D;Yakovlev A
本研究的目的是提高抗生素的抗生物被膜活性。我们假设宿主免疫系统的抗菌肽（AMP）复合物可用于此目的，并研究了模型生物膜的假设。FLIP 7是拟丽蝇的AMP复合物，含有防御素、天蚕素、双蝶素和富含脯氨酸的肽的组合，从细菌攻击的蛆的血淋巴中分离。通过棋盘法，使用氯化三甲基四氮唑细胞活力和结晶紫生物膜根除试验，并辅以显微镜分析，研究了金黄色葡萄球菌、大肠杆菌、铜绿假单胞菌、肺炎克雷伯菌和鲍曼不动杆菌的生物膜和增殖培养物中与各类抗生素的复杂相互作用。我们发现FLIP 7表现出：与美罗培南、阿米卡星、卡那霉素、氨苄青霉素、万古霉素和头孢噻肟的高协同作用（部分抑制浓度指数<0.25）;与克林霉素、红霉素和氯霉素的协同作用;与苯唑西林、四环素、环丙沙星和庆大霉素的相加相互作用;以及与多粘菌素B没有相互作用。浮游细胞模型中的相互作用明显弱于相同菌株的生物膜。剂量-效应曲线的分析指出持续存在的细胞是FLIP 7协同效应的可能靶标。生物膜清除试验表明，该作用也导致S. aureus和E. coli生物膜材料。该作用允许将抗生素的有效抗生物膜浓度降低至远低于临床可实现的水平（在美罗培南、氨苄西林、头孢噻肟和苯唑西林的情况下为2-3个数量级）。FLIP 7是一种高效的宿主抗菌系统，通过对持留菌的致敏作用和对生物膜物质的破坏，帮助抗生素克服生物膜屏障。它作为各种小分子抗生素的辅助治疗生物被膜感染是有希望的。
The aim of this study is to improve the anti-biofilm activity of antibiotics. We hypothesized that the antimicrobial peptide (AMP) complex of the host’s immune system can be used for this purpose and examined the assumption on model biofilms. FLIP7, the AMP complex of the blowfly Calliphora vicina containing a combination of defensins, cecropins, diptericins and proline-rich peptides was isolated from the hemolymph of bacteria-challenged maggots. The complex interaction with antibiotics of various classes was studied in biofilm and planktonic cultures of Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii by the checkerboard method using trimethyl tetrazolium chloride cell viability and crystal violet biofilm eradication assays supplemented with microscopic analysis. We found that FLIP7 demonstrated: high synergy (fractional inhibitory concentration index <0.25) with meropenem, amikacin, kanamycin, ampicillin, vancomycin and cefotaxime; synergy with clindamycin, erythromycin and chloramphenicol; additive interaction with oxacillin, tetracycline, ciprofloxacin and gentamicin; and no interaction with polymyxin B. The interaction in planktonic cell models was significantly weaker than in biofilms of the same strains. The analysis of the dose–effect curves pointed to persister cells as a likely target of FLIP7 synergistic effect. The biofilm eradication assay showed that the effect also caused total destruction of S. aureus and E. coli biofilm materials. The effect allowed reducing the effective anti-biofilm concentration of the antibiotic to a level well below the one clinically achievable (2–3 orders of magnitude in the case of meropenem, ampicillin, cefotaxime and oxacillin). FLIP7 is a highly efficient host antimicrobial system helping antibiotics to overcome biofilm barriers through persisters’ sensitization and biofilm material destruction. It is promising for the treatment of biofilm infections as an adjuvant of various small-molecule antibiotics.