Selection of a multidrug resistance plasmid by sublethal levels of antibiotics and heavy metals.
Selection of a multidrug resistance plasmid by sublethal levels of antibiotics and heavy metals.
复制标题
DOI：
10.1128/mbio.01918-14
复制
发表时间：
2014-10-07
期刊：
影响因子：
6.4
通讯作者：
Andersson DI
中科院分区：
文献类型：
--
作者：
Gullberg E;Albrecht LM;Karlsson C;Sandegren L;Andersson DI
亚致死水平的抗生素和重金属如何选择临床上重要的多药耐药质粒在很大程度上是未知的。质粒的携带通常赋予相当大的适应性成本，这意味着为了使携带质粒的细菌维持在群体中，质粒成本需要通过由例如抗生素或重金属赋予的选择压力来平衡。我们研究了低水平抗生素和重金属对在医院肺炎克雷伯菌和大肠埃希菌爆发中鉴定的220 kbp超广谱β-内酰胺酶（ESBL）质粒选择性维持的影响。维持携带质粒的细菌所需的抗生素和重金属的浓度，即最小选择浓度（MSC），在所有情况下均低于（几乎高达140倍）无质粒敏感细菌的MIC。这一发现表明，在污染的环境中以及在治疗的人类和动物中发现的非常低的抗生素和重金属水平可能足够高以维持多重耐药性质粒。当抗性基因从质粒转移到染色体上时，MSC减少，表明MSC的特异性抗性有条件地取决于遗传背景。这一发现表明，一个免费的耐药性可以保持在一个人口的无限低浓度的抗生素。通过研究几种化合物组合的效果，观察到对于某些药物组合，每种新化合物的加入降低了其他化合物的最小选择浓度。这种组合效应可能是在复杂的多药环境中选择多药耐药质粒/细菌克隆的重要因素。抗生素耐药性在许多病原菌中是由大接合质粒上携带的基因引起的。这些质粒通常含有多种抗生素抗性基因以及赋予对杀生物剂和重金属抗性的基因。在这份报告中，我们表明，非常低浓度的单一抗生素和重金属或化合物的组合可以选择一个大的质粒，携带耐药性的氨基糖苷类，β-内酰胺类，四环素，大环内酯类，甲氧苄啶，磺胺，银，铜，砷。我们的研究结果表明，低水平的抗生素和重金属存在于污染的外部环境中，并在治疗的动物和人类可以允许选择和富集的细菌与多重耐药质粒，从而有助于出现，维护和传播的耐药性致病细菌。
How sublethal levels of antibiotics and heavy metals select for clinically important multidrug resistance plasmids is largely unknown. Carriage of plasmids generally confers substantial fitness costs, implying that for the plasmid-carrying bacteria to be maintained in the population, the plasmid cost needs to be balanced by a selective pressure conferred by, for example, antibiotics or heavy metals. We studied the effects of low levels of antibiotics and heavy metals on the selective maintenance of a 220-kbp extended-spectrum β-lactamase (ESBL) plasmid identified in a hospital outbreak of Klebsiella pneumoniae and Escherichia coli. The concentrations of antibiotics and heavy metals required to maintain plasmid-carrying bacteria, the minimal selective concentrations (MSCs), were in all cases below (almost up to 140-fold) the MIC of the plasmid-free susceptible bacteria. This finding indicates that the very low antibiotic and heavy metal levels found in polluted environments and in treated humans and animals might be sufficiently high to maintain multiresistance plasmids. When resistance genes were moved from the plasmid to the chromosome, the MSC decreased, showing that MSC for a specific resistance conditionally depends on genetic context. This finding suggests that a cost-free resistance could be maintained in a population by an infinitesimally low concentration of antibiotic. By studying the effect of combinations of several compounds, it was observed that for certain combinations of drugs each new compound added lowered the minimal selective concentration of the others. This combination effect could be a significant factor in the selection of multidrug resistance plasmids/bacterial clones in complex multidrug environments. Antibiotic resistance is in many pathogenic bacteria caused by genes that are carried on large conjugative plasmids. These plasmids typically contain multiple antibiotic resistance genes as well as genes that confer resistance to biocides and heavy metals. In this report, we show that very low concentrations of single antibiotics and heavy metals or combinations of compounds can select for a large plasmid that carries resistance to aminoglycosides, β-lactams, tetracycline, macrolides, trimethoprim, sulfonamide, silver, copper, and arsenic. Our findings suggest that the low levels of antibiotics and heavy metals present in polluted external environments and in treated animals and humans could allow for selection and enrichment of bacteria with multiresistance plasmids and thereby contribute to the emergence, maintenance, and transmission of antibiotic-resistant disease-causing bacteria.