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科学家发现基因突变导致抗生素耐药性 翻译：刘金淑（濮阳市油田总医院） 审核：陈志锦 发布新闻 抗生素耐药性研究 麻省理工和哈佛大学博德研究院的科学家们已经确定了新的细菌突变,促进高级抗生素耐药性的进化。研究结果发表在《电子信息时代生活》,增进了我们对抗生素耐药性如何发展的了解。研究团队声称，对维持现有和未来药物的有效性，这至关重要。 耐药性细菌的上升，对临床医生很具有挑战性,某些感染已经抵抗几乎所有可用的药物。2013年美国疾病控制和预防中心评估的一份报告称, 仅在美国耐药菌感染每年致死人数就达23000人之多。 当前研究组核心成员资深作者和博德研究院传染病与微生物项目联合主任黛博拉·亨说:“某些种类的细菌,包括分枝杆菌，是耐药性基因突变的结果。我们想通过查看抵抗抗生素浓度之间的关系,其杀菌效果及耐药突变体的出现，对分子过程有一个新的认识。” 要做到这一点,亨和她的团队培养了数以百计的培植物种的耻垢分枝杆菌 (m . smegmatis),即引发结核病的结核杆菌同类，揭示了细菌抗生素浓度低,药物的微生物杀灭效果相对较慢的现状。这引导团队在监控敏感细菌死亡的同时，孤立形成突变体源泉。 第一作者詹姆斯·戈麦斯说，“我们发现耐药突变的结果是我们培养的一小部分,” “在不同核糖体组分里，每个单体都形成了单一突变，复杂分子机器负责构建细胞内的蛋白质。” 研究小组发现,这些新核糖体基因突变使细菌抵抗几个不同类型的抗生素,甚至无法针对核糖体，突变体也从未出现。他们同样增强抵抗两个非抗性压力:热休克和薄膜应力。 戈麦斯解释说:“我们看到了适合度成本，突变体降低了细菌增长率。然而,伴随突变发生在细胞的重组，使细菌对抗生素和非抗性压力的敏感度均大大降低。这表明,在耻垢分枝杆菌等物种里，尽管突变成本呈上升趋势，这些类型的突变可以在多种药品环境下提高适合度，并作为垫脚石向高等级耐药性能发展。” 团队现在想探究这一现象，把不同的细菌物种,包括结核分枝杆菌,通过耦合实验生物学方法，对基因序列信息进行彻底的探索。对多药耐药性的出现有一个更完整的了解，可以帮助开发或优化新的治疗细菌感染的药物。 来源:电子信息时代生活 Scientists Find Genetic Mutations That Drive Antibiotic Resistance 15 hours ago Comments Posted in News, Antibiotic Resistance, Research Print Scientists from the Broad Institute of MIT and Harvard University have identified novel mutations in bacteria that promote the evolution of high-level antibiotic resistance. The findings, published in eLife, add to our understanding of how antibiotic resistance develops, which the team says is crucial for maintaining the effectiveness of both existing and future drugs.
The rise of antibiotic-resistant bacteria is challenging clinicians, with some infections already resistant to nearly all available drugs. A 2013 report from the Centers for Disease Control and Prevention estimates that such infections kill at least 23,000 people each year in the United States alone*.
Deborah Hung, senior author of the current study and Core Institute Member and Co-Director of the Infectious Disease and Microbiome Program at the Broad Institute, says: "Some species of bacteria, including mycobacteria, develop drug resistance as a result of mutations in their genes. We wanted to gain new insight into the molecular processes that promote resistance in these species by looking at the relationships between the concentration of antibiotics, their killing effects on bacteria, and the emergence of drug-resistant mutants."
To do this, Hung and her team grew hundreds of cultures of the species Mycobacterium smegmatis (M. smegmatis), a cousin of the bacterium that causes tuberculosis. They exposed the bacteria to low antibiotic concentrations, where the drugs' microbe-killing effects were relatively slow. This allowed the team to monitor the killing of sensitive bacteria while isolating individual wells where mutants developed.
"We detected the outgrowth of drug-resistant mutants in a fraction of our cultures," says first author James Gomez. "Each individual carried single mutations in different components of the ribosome, the complex molecular machine responsible for building proteins within cells."
The team found that these novel ribosomal mutations granted the bacteria resistance to several different classes of antibiotics that do not even target the ribosome, and to which the mutants had never been exposed. They also enhanced resistance to two non-antibiotic stresses: heat shock and membrane stress.
Gomez explains: "We did see a fitness cost to the bacteria in that the mutations reduced their growth rate. However, the reprogramming that occurred within the cells in response to the mutations made the bacteria much less sensitive to both antibiotic and non-antibiotic stresses. This suggests that, in species such as M. smegmatis, these types of mutations can enhance fitness in multidrug environments and serve as stepping stones toward the development of high-level drug resistance, despite the cost that the mutations have on growth."
The team now wants to explore this phenomenon across diverse bacterial species, including Mycobacterium tuberculosis, by coupling experimental biological approaches with a thorough exploration of genome sequence information. A more complete understanding of how multidrug resistance emerges could help in the development or optimization of new drugs for treating bacterial infections.
Source: eLife 图文编辑：朱迪 审稿：高晓东/马嘉睿 | 
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