Using a sequential regimen to eliminate bacteria at sublethal antibiotic dosages.
Using a sequential regimen to eliminate bacteria at sublethal antibiotic dosages.
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DOI：
10.1371/journal.pbio.1002104
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发表时间：
2015-04
期刊：
影响因子：
9.8
通讯作者：
Beardmore R
中科院分区：
文献类型：
--
作者：
Fuentes-Hernandez A;Plucain J;Gori F;Pena-Miller R;Reding C;Jansen G;Schulenburg H;Gudelj I;Beardmore R
我们需要找到增强现有抗生素效力的方法，考虑到这一点，我们开始一个不寻常的问题：抗生素剂量可以低到多低，但仍然可以观察到细菌清除？为了优化两种抗生素的同时使用，我们使用在抗生素治疗的体外实验模型中观察到的清除率的最小剂量作为区分细菌大肠杆菌的最佳和最差治疗的标准。我们的目的是比较由两种协同抗生素组成的联合治疗与所谓的序贯治疗，其中抗生素的选择可以随着每一轮治疗而改变。使用经E.大肠杆菌治疗模型，我们表明，清除细菌可以实现使用顺序治疗的抗生素剂量如此之低，相当于两种药物的组合治疗是无效的。为了在实验环境中处理该菌，我们有目的地对一株大肠杆菌进行了研究。一种大肠杆菌菌株，其染色体中编码了一种多药泵，可以排出两种抗生素。基因组扩增增加了每个细胞表达的泵的数量，这可能导致高剂量组合治疗的失败，然而，正如我们所展示的，连续治疗的群体仍然可以崩溃。然而，由于泵引起的双重耐药性意味着抗生素必须小心部署，并且并非所有亚致死顺序治疗都成功。对136个96小时长的连续处理进行筛选，确定了其中5个可以在所有重复群体中清除亚致死剂量的细菌，尽管在24小时之前没有一个这样做。这些成功可归因于附带敏感性，其中由于双重泵引起的交叉电阻证明不足以阻止E的减少。药物交换后大肠杆菌的生长速度，证明这种降低足够大，可以适当选择药物开关来清除细菌。实验室治疗模型表明，可以优化两种抗生素的顺序交替使用，以优于等效剂量的联合治疗。所谓的“鸡尾酒”疗法通常被认为是一种增强抗生素效力的方法，其基础是多种药物作为单一联合疗法的一部分一起使用时可以协同作用。我们调查了是否有其他的多药部署策略在降低细菌密度方面与协同抗生素组合一样有效，甚至可能更好。抗生素之间的“附带敏感性”经常被观察到;这是当细菌采取措施对抗一种抗生素的存在时，它对随后使用的另一种抗生素敏感。我们的方法是看看我们是否可以利用这些敏感性，首先部署一种药物，然后删除它，而不是部署另一种药物，然后重复这个过程。这并不是一个全新的想法，而且这种治疗形式在临床上已经被用于幽门螺杆菌感染的试验。我们在这里追求的想法是“序贯治疗”的延伸;我们研究了是否有两种抗生素和n轮治疗，如果我们在所有可能的2n“序贯治疗”集合中搜索-包括两种单药单药疗法-在该集合中可能有比等效的两种药物鸡尾酒更有效的治疗。使用一个简单的体外治疗模型，我们表明，一些顺序的时间抗生素治疗是成功的条件下，导致失败的鸡尾酒治疗时，在同等剂量实施。
We need to find ways of enhancing the potency of existing antibiotics, and, with this in mind, we begin with an unusual question: how low can antibiotic dosages be and yet bacterial clearance still be observed? Seeking to optimise the simultaneous use of two antibiotics, we use the minimal dose at which clearance is observed in an in vitro experimental model of antibiotic treatment as a criterion to distinguish the best and worst treatments of a bacterium, Escherichia coli. Our aim is to compare a combination treatment consisting of two synergistic antibiotics to so-called sequential treatments in which the choice of antibiotic to administer can change with each round of treatment. Using mathematical predictions validated by the E. coli treatment model, we show that clearance of the bacterium can be achieved using sequential treatments at antibiotic dosages so low that the equivalent two-drug combination treatments are ineffective. Seeking to treat the bacterium in testing circumstances, we purposefully study an E. coli strain that has a multidrug pump encoded in its chromosome that effluxes both antibiotics. Genomic amplifications that increase the number of pumps expressed per cell can cause the failure of high-dose combination treatments, yet, as we show, sequentially treated populations can still collapse. However, dual resistance due to the pump means that the antibiotics must be carefully deployed and not all sublethal sequential treatments succeed. A screen of 136 96-h-long sequential treatments determined five of these that could clear the bacterium at sublethal dosages in all replicate populations, even though none had done so by 24 h. These successes can be attributed to a collateral sensitivity whereby cross-resistance due to the duplicated pump proves insufficient to stop a reduction in E. coli growth rate following drug exchanges, a reduction that proves large enough for appropriately chosen drug switches to clear the bacterium. A laboratory treatment model shows that the sequentially alternating use of two antibiotics can be optimized to outperform combination treatments at the equivalent dose. So-called “cocktail” treatments are often proposed as a way of enhancing the potency of antibiotics, based on the idea that multiple drugs can synergise when used together as part of a single combined therapy. We investigated whether any other multidrug deployment strategies are as effective as—or perhaps even better than—synergistic antibiotic combinations at reducing bacterial densities. “Collateral sensitivities” between antibiotics are frequently observed; this is when measures taken by a bacterium to counter the presence of one antibiotic sensitise it to the subsequent use of another. Our approach was to see if we could exploit these sensitivities by first deploying one drug, then removing it and instead deploying another, and then repeating this process. This is not an entirely new idea, and there is a precedence for this form of treatment that has been trialled in the clinic for Helicobacter pylori infection. The idea we pursued here is an extension of “sequential treatment”; we investigated whether with two antibiotics and n rounds of treatment, if we search within the set of all possible 2 n “sequential treatments”—including the two single-drug monotherapies—there might be treatments within that set that are more effective than the equivalent two-drug cocktail. Using a simple in vitro treatment model, we show that some sequential-in-time antibiotic treatments are successful under conditions that cause the failure of the cocktail treatment when implemented at the equivalent dosage.
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影响因子：
6.7
作者：
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