PLoS Biol:交替使用抗生素可有效“打击”耐药性的细菌
来源:生物谷 2015-04-14 10:52
近日,一项刊登在国际杂志PLoS Biology上的研究论文中,来自埃克塞特大学的研究人员通过研究揭开了一种新型技术,其可以帮助抵御抗生素耐药性细菌增长的趋势,耐药性细菌会引发机体患病而且通常会引发威胁生命的疾病。
2015年4月14日 讯 /生物谷BIOON/ --近日,一项刊登在国际杂志PLoS Biology上的研究论文中,来自埃克塞特大学的研究人员通过研究揭开了一种新型技术,其可以帮助抵御抗生素耐药性细菌增长的趋势,耐药性细菌会引发机体患病而且通常会引发威胁生命的疾病。
研究者利用了一种序贯疗法,即利用交替剂量的抗生素来有效抵御细菌的感染;这种进行疗法管理的技术可以降低细菌对抗生素产生耐药性的风险,同时也可以维持药物的长期效力。研究表明,利用两种抗生素的药物疗法或许会以一定剂量杀灭细菌,而这种药物剂量通常也会促进细菌药物耐受性的快速产生,并且维持细菌的生长。
文章中研究者利用了一种检测管模型来阐明细菌的感染过程,甚至是在细菌已经拥有许多耐药性基因的同时,这种序贯疗法都可以治疗细菌感染,甚至当大剂量的单一药物或两种药物混合时该疗法也可以发挥作用。Beardmore教授说道,我们的研究揭示了药物剂量、细菌菌落密度及药物抗性之间的复杂关系,正如研究发现,我们就有可能将细菌的药物负载降低为零,也就是通常所说的药物处于亚致死剂量状态,这或许就被假定为进行药物耐受性增加的选择。
研究者同时发现,尽管序贯疗法不能抑制细菌所有药物耐受性突变的增加,但一种药物或许可以促进细菌对第二种药物敏感,从而降低耐药性发生的风险;研究者已经对协同药物鸡尾酒疗法进行了长期的研究,他们认为这种连续的协同作用是非常有效的,而这一研究或许也会赢得许多制药公司的关注和兴趣。
当细菌作为主人适应抗生素挑战时,研究者就会利用这种适应性机制去对付细菌,由事先设计好的序贯疗法产生的波动环境就会促进细菌对药物敏感,从而致使细菌对抗生素的浓度变得敏感。研究者表示,尽管后期还需有许多工作要做,但本文研究揭示了,当所用药物剂量低于最大效力时序贯疗法或许是最为有效的;本文研究获将帮助研究者们后期进行一系列的研究来确定使用抗生素的方法,不仅仅是单独使用抗生素,而是连续性地以低于当前认为剂量的药物进行治疗和研究。(生物谷Bioon.com)
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Using a Sequential Regimen to Eliminate Bacteria at Sublethal Antibiotic Dosages
Fuentes-Hernandez A, Plucain J, Gori F, Pena-Miller R, Reding C, et al.
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.
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