Surfaces modified with small molecules that interfere with nucleotide signaling reduce Staphylococcus epidermidis biofilm and increase the efficacy of ciprofloxacin.
Surfaces modified with small molecules that interfere with nucleotide signaling reduce Staphylococcus epidermidis biofilm and increase the efficacy of ciprofloxacin.
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DOI：
10.1016/j.colsurfb.2023.113345
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发表时间：
2023-05
期刊：
影响因子：
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通讯作者：
Li-Chong Xu;Alyssa Ochetto;Chen Chen-Chen;Dongxiao Sun;H. Allcock;C. Siedlecki
中科院分区：
文献类型：
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作者：
Li-Chong Xu;Alyssa Ochetto;Chen Chen-Chen;Dongxiao Sun;H. Allcock;C. Siedlecki
表皮葡萄球菌是与植入式医疗器械上的生物膜相关感染相关的常见细菌。抗生素通常用于对抗此类感染，但它们可能在生物膜的存在下失去功效。细菌细胞内核苷酸第二信使信号在生物膜形成中起着重要作用，干扰核苷酸信号通路为控制生物膜形成和增加生物膜对抗生素治疗的敏感性提供了可能的途径。本文合成了4-芳基偶氮-3，5-二氨基-1H-吡唑的小分子衍生物（SP 02和SP 03），发现它们对S.表皮生物膜形成和诱导的生物膜分散。对细菌核苷酸信号分子的分析表明，SP 02和SP 03在低至25 μM的剂量下显著降低表皮葡萄球菌中的环二聚腺苷一磷酸（c-di-AMP）水平，而在高剂量（100 μM或更高）下对包括环二聚鸟苷一磷酸（c-di-GMP）、c-di-AMP和环腺苷一磷酸（cAMP）的多核苷酸信号具有显著影响。然后，我们将这些小分子拴系到聚氨酯（PU）生物材料表面，并研究改性表面上的生物膜形成。结果表明，在24小时和7天的培养过程中，改性表面显着抑制生物膜的形成。使用抗生素环丙沙星处理这些生物膜，发现抗生素（2 μg/mL）的功效从未改性PU表面上的94.8%增加到SP 02和SP 03改性表面上的> 99.9%（>3 log单位）。结果证明了将干扰核苷酸信号传导的小分子拴系到聚合物生物材料表面上的可行性，并且以中断生物膜形成并增加对S的抗生素功效的方式。表皮消毒
Staphylococcus epidermidisare common bacteria associated with biofilm related infections on implanted medical devices. Antibiotics are often used in combating such infections, but they may lose their efficacy in the presence of biofilms. Bacterial intracellular nucleotide second messenger signaling plays an important role in biofilm formation, and interference with the nucleotide signaling pathways provides a possible way to control biofilm formation and to increase biofilm susceptibility to antibiotic therapy. This study synthesized small molecule derivates of 4-arylazo-3,5-diamino-1 H-pyrazole (named as SP02 and SP03) and found these molecules inhibitedS. epidermidisbiofilm formation and induced biofilm dispersal. Analysis of bacterial nucleotide signaling molecules showed that both SP02 and SP03 significantly reduced cyclic dimeric adenosine monophosphate (c-di-AMP) levels inS. epidermidisat doses as low as 25 µM while having significant effects on multiple nucleotides signaling including cyclic dimeric guanosine monophosphate (c-di-GMP), c-di-AMP, and cyclic adenosine monophosphate (cAMP) at high doses (100 µM or greater). We then tethered these small molecules to polyurethane (PU) biomaterial surfaces and investigated biofilm formation on the modified surfaces. Results showed that the modified surfaces significantly inhibited biofilm formation during 24 h and 7-day incubations. The antibiotic ciprofloxacin was used to treat these biofilms and the efficacy of the antibiotic (2 µg/mL) was found to increase from 94.8% on unmodified PU surfaces to > 99.9% on both SP02 and SP03 modified surfaces (>3 log units). Results demonstrated the feasibility of tethering small molecules that interfere with nucleotide signaling onto polymeric biomaterial surfaces and in a way that interrupts biofilm formation and increases antibiotic efficacy forS. epidermidisinfections.