Inter-species population dynamics enhance microbial horizontal gene transfer and spread of antibiotic resistance.
Inter-species population dynamics enhance microbial horizontal gene transfer and spread of antibiotic resistance.
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DOI：
10.7554/elife.25950
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发表时间：
2017-11-01
期刊：
影响因子：
7.7
通讯作者：
Hasty J
中科院分区：
文献类型：
--
作者：
Cooper RM;Tsimring L;Hasty J
水平基因转移（HGT）在抗生素抗性的传播中起着重要作用。鲍曼不动杆菌尤其令人担忧，它最近作为全球性病原体出现，医院内死亡率达到19% - 54%（美国疾病控制与预防中心，2013年；若利·吉尤，2005年；塔尔博特等人，2006年）。不动杆菌获得抗生素抗性的速度非常快（安图内斯等人，2014年；若利·吉尤，2005年），多重耐药（MDR）率超过60%（安图内斯等人，2014年；美国疾病控制与预防中心，2013年）。尽管人们越来越担忧（美国疾病控制与预防中心，2013年；塔尔博特等人，2006年），但这种广泛的HGT背后的机制仍知之甚少（亚当斯等人，2008年；富尼耶等人，2006年；因佩里等人，2011年；拉米雷斯等人，2010年；威尔哈姆等人，2013年）。在此，我们表明贝氏不动杆菌的细菌捕食行为使跨物种HGT增加了几个数量级，并且我们观察到捕食细胞从邻近的猎物功能性地获取适应性抗性基因。然后我们开发了一个种群动态模型，用于量化固体表面上的杀伤和HGT。我们表明通过细胞裂解释放的DNA很容易用于HGT，并且可能在一定程度上受到环境的保护，描述了细胞密度的影响，并评估了潜在的环境抑制剂。这些发现为理解、量化和对抗微生物组内的HGT以及多重耐药超级细菌的出现建立了一个框架。
每年，抗生素拯救数百万条生命，但这种情况可能不会永远持续下去。引起感染的细菌变得越来越聪明，并不断进化基因以对抗生素产生抗性，这使得杀死它们变得更加困难。在许多情况下，使用更强的药物可以绕过这个问题，但一些“超级细菌”对我们现有的每一种药物都产生了抗性。例如，鲍曼不动杆菌最近被列为全球性威胁，每年导致数千人死亡，使其位于多重耐药细菌的六大“头号通缉犯”名单之上。令人担忧的是，这种耐药性的发展似乎比“标准”进化所允许的速度更快，这使得跟上开发新的有效药物的步伐变得困难。
细菌能够缩短抗性进化的一种方式是通过一种称为水平基因转移的过程，在这个过程中它们从其他细菌收集抗性基因。一些细菌可以通过主动杀死它们的邻居以提取其DNA来加速这种基因转移。然而，直到现在，这个过程还没有被直接观察到，并且在何时何地杀死邻居对基因转移变得重要也没有被完全理解。
现在，库珀、齐姆林和黑斯蒂研究了鲍曼不动杆菌的一个近亲，称为贝氏不动杆菌。将贝氏不动杆菌与另一种含有绿色荧光基因的细菌一起放在一个允许两种细菌生长的表面上。随着这两种细菌一起生长，贝氏不动杆菌开始杀死另一种细菌并窃取它们的基因。这种情况发生得如此频繁，以至于一些细菌开始发出荧光，这可以在显微镜下实时观察到。贝氏不动杆菌还窃取了抗生素抗性基因，当加入一种抗生素时，带有窃取的抗性基因的细菌继续生长和分裂，而其他细菌则被杀死。
库珀等人随后开发了一个数学模型来量化和模拟这种因杀伤而增强的水平基因转移。结果表明，当贝氏不动杆菌的数量较多且“受害者”的数量较少时——以及当它们在一起的时间较短时，杀死其他细菌会使基因转移更有效。
这项工作可能有助于解释不动杆菌和类似细菌如何如此迅速地产生耐药性。下一步将是测量和比较不同类型细菌的基因转移参数。更好地理解基因转移如何、在何处以及何时发生，可能在未来有助于指导对抗耐药性的策略。
Horizontal gene transfer (HGT) plays a major role in the spread of antibiotic resistance. Of particular concern are Acinetobacter baumannii bacteria, which recently emerged as global pathogens, with nosocomial mortality rates reaching 19–54% (Centers for Disease Control and Prevention, 2013; Joly Guillou, 2005; Talbot et al., 2006). Acinetobacter gains antibiotic resistance remarkably rapidly (Antunes et al., 2014; Joly Guillou, 2005), with multi drug-resistance (MDR) rates exceeding 60% (Antunes et al., 2014; Centers for Disease Control and Prevention, 2013). Despite growing concern (Centers for Disease Control and Prevention, 2013; Talbot et al., 2006), the mechanisms underlying this extensive HGT remain poorly understood (Adams et al., 2008; Fournier et al., 2006; Imperi et al., 2011; Ramirez et al., 2010; Wilharm et al., 2013). Here, we show bacterial predation by Acinetobacter baylyi increases cross-species HGT by orders of magnitude, and we observe predator cells functionally acquiring adaptive resistance genes from adjacent prey. We then develop a population-dynamic model quantifying killing and HGT on solid surfaces. We show DNA released via cell lysis is readily available for HGT and may be partially protected from the environment, describe the effects of cell density, and evaluate potential environmental inhibitors. These findings establish a framework for understanding, quantifying, and combating HGT within the microbiome and the emergence of MDR super-bugs. Every year, antibiotics save millions of lives, but this may not last forever. The bacteria that cause infections are getting smarter and continuously evolve genes to become resistant to antibiotics, which makes it harder to kill them. In many cases, using stronger drugs can bypass this problem, but some 'super-bugs' are developing resistance to every drug we have. For example, the bacterium Acinetobacter baumannii has recently been classified as a global threat that kills thousands of people every year, which placed it on a top six 'most wanted' list for multi drug-resistant bacteria. Worryingly, this drug resistance seems to develop faster than 'standard' evolution would allow, making it difficult to keep up with developing new effective drugs. One way bacteria can shortcut the evolution of resistance is through a process called horizontal gene transfer, in which they collect resistance genes from other bacteria. Some bacteria can speed up this gene transfer by actively killing their neighbors to extract their DNA. However, until now, this process has not been observed directly, and it was not fully understood where and when killing neighbors becomes important for gene transfer. Now, Cooper, Tsimring and Hasty have studied a relative of A. baumannii called A. baylyi. Together with another type of bacteria that contained green fluorescence genes, A. baylyi was placed onto a surface that allowed both species to grow. As the two types of bacteria grew together, A. baylyi started to kill the other one and stole their genes. This happened so often that some started to become fluorescent, which could be observed in real time under a microscope. A. baylyi also stole genes for antibiotic resistance, and when an antibiotic was added, the bacteria with the stolen resistance genes kept growing and dividing, while the others were killed. Cooper et al. then developed a mathematical model to quantify and simulate this killing-enhanced horizontal gene transfer. The results showed that killing other bacteria made gene transfer more effective when the number of A. baylyi was high and the number of 'victims' was low – and also when they were together for a shorter period. This work may help to explain how Acinetobacter and similar bacteria develop drug resistance so quickly. A next step will be to measure and compare gene transfer parameters in different types of bacteria. A better understanding of how, where, and when gene transfer happens, may in the future help to guide strategies to fight resistance.