Aminoglycoside antibiotics induce bacterial biofilm formation
Aminoglycoside antibiotics induce bacterial biofilm formation
复制标题
DOI：
10.1038/nature03912
复制
发表时间：
2005-08-25
期刊：
影响因子：
64.8
通讯作者：
Miller, SI
中科院分区：
文献类型：
--
作者：
Hoffman, LR;D'Argenio, DA;Miller, SI
生物膜是在生物和非生物表面（包括人体组织）上形成的细菌细胞的粘附聚集体。生物膜抵抗抗生素治疗并导致慢性感染中的细菌持续存在(1,2)。因此，阐明生物膜形成的机制可能有助于治疗慢性感染，例如囊性纤维化患者气道中的铜绿假单胞菌(2)。在这里，我们发现亚抑制浓度的氨基糖苷类抗生素会诱导铜绿假单胞菌和大肠杆菌生物膜的形成。在铜绿假单胞菌中，我们将其命名为氨基糖苷反应调节因子（arr）的基因对于这种诱导至关重要，并且有助于生物膜特异性氨基糖苷抗性。 arr 基因预计会编码一种内膜磷酸二酯酶，其底物是环二鸟苷单磷酸 (c-di-GMP)，这是一种调节细胞表面粘附性的细菌第二信使 (3)。我们发现，arr 突变体的膜降低了 c-di-GMP 磷酸二酯酶活性，并且具有改变 Arr 预测催化残基的突变的铜绿假单胞菌细胞在其生物膜对妥布霉素的反应中存在缺陷。此外，妥布霉素诱导的生物膜形成受到外源 GTP 的抑制，已知外源 GTP 会抑制 c-di-GMP 磷酸二酯酶活性 (4)。我们的结果表明，生物膜的形成可能是对抗生素存在的一种特异性防御反应，并表明这种反应的分子基础包括 c-di-GMP 水平的改变。
Biofilms are adherent aggregates of bacterial cells that form on biotic and abiotic surfaces, including human tissues. Biofilms resist antibiotic treatment and contribute to bacterial persistence in chronic infections(1,2). Hence, the elucidation of the mechanisms by which biofilms are formed may assist in the treatment of chronic infections, such as Pseudomonas aeruginosa in the airways of patients with cystic fibrosis(2). Here we show that subinhibitory concentrations of aminoglycoside antibiotics induce biofilm formation in P. aeruginosa and Escherichia coli. In P. aeruginosa, a gene, which we designated aminoglycoside response regulator (arr), was essential for this induction and contributed to biofilm-specific aminoglycoside resistance. The arr gene is predicted to encode an inner-membrane phosphodiesterase whose substrate is cyclic di-guanosine monophosphate (c-di-GMP) - a bacterial second messenger that regulates cell surface adhesiveness(3). We found that membranes from arr mutants had diminished c-di-GMP phosphodiesterase activity, and P. aeruginosa cells with a mutation changing a predicted catalytic residue of Arr were defective in their biofilm response to tobramycin. Furthermore, tobramycin-inducible biofilm formation was inhibited by exogenous GTP, which is known to inhibit c-di-GMP phosphodiesterase activity(4). Our results demonstrate that biofilm formation can be a specific, defensive reaction to the presence of antibiotics, and indicate that the molecular basis of this response includes alterations in the level of c-di-GMP.