Exploiting adaptive laboratory evolution of Streptomyces clavuligerus for antibiotic discovery and overproduction.
Exploiting adaptive laboratory evolution of Streptomyces clavuligerus for antibiotic discovery and overproduction.
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DOI：
10.1371/journal.pone.0033727
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Palsson BO
中科院分区：
文献类型：
--
作者：
Charusanti P;Fong NL;Nagarajan H;Pereira AR;Li HJ;Abate EA;Su Y;Gerwick WH;Palsson BO
适应通常被视为抗生素发现和开发过程的敌人，因为病原体对抗生素暴露的适应导致耐药性。相反，我们在这里提出了一种方法，利用抗生素生产商的适应能力来加速抗生素的发现。提出了一种基于竞争的适应性实验室进化方案，其中，产生病原体的微生物与目标病原体竞争，并随着时间的推移连续通过，直到生产者进化出合成抑制病原体生长的化学实体的能力。当多个棒状链霉菌重复以这种方式适应性进化对抗耐甲氧西林金黄色葡萄球菌N315时，出现了获得组成型产生全霉素的能力的菌株。相比之下，未进化的野生型菌株中未检测到全霉素。此外，基因组重新测序显示，进化菌株已经失去了pSCL 4，一个大的1.8 Mbp的质粒，并获得了几个单核苷酸多态性的基因，已被证明会影响次级代谢产物的生物合成。这些结果表明，基于竞争的适应性实验室进化可以构成一个平台，以创建过量生产已知抗生素的突变体，并可能发现新的化合物。
Adaptation is normally viewed as the enemy of the antibiotic discovery and development process because adaptation among pathogens to antibiotic exposure leads to resistance. We present a method here that, in contrast, exploits the power of adaptation among antibiotic producers to accelerate the discovery of antibiotics. A competition-based adaptive laboratory evolution scheme is presented whereby an antibiotic-producing microorganism is competed against a target pathogen and serially passed over time until the producer evolves the ability to synthesize a chemical entity that inhibits growth of the pathogen. When multiple Streptomyces clavuligerus replicates were adaptively evolved against methicillin-resistant Staphylococcus aureus N315 in this manner, a strain emerged that acquired the ability to constitutively produce holomycin. In contrast, no holomycin could be detected from the unevolved wild-type strain. Moreover, genome re-sequencing revealed that the evolved strain had lost pSCL4, a large 1.8 Mbp plasmid, and acquired several single nucleotide polymorphisms in genes that have been shown to affect secondary metabolite biosynthesis. These results demonstrate that competition-based adaptive laboratory evolution can constitute a platform to create mutants that overproduce known antibiotics and possibly to discover new compounds as well.
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影响因子：
4.5
作者：
Charusanti P;Conrad TM;Knight EM;Venkataraman K;Fong NL;Xie B;Gao Y;Palsson BØ
通讯作者：
Palsson BØ
影响因子：
5.2
作者：
BERGERBACHI, B;STRASSLE, A;KAYSER, FH
通讯作者：
KAYSER, FH
影响因子：
2.8
作者：
Gottelt, Marco;Kol, Stefan;Takano, Eriko
通讯作者：
Takano, Eriko
DOI：
10.1016/j.bbrc.2009.12.013
发表时间：
2010-01-01
影响因子：
3.1
作者：
Hu, Hongbo;Wood, Thomas K.
通讯作者：
Wood, Thomas K.
影响因子：
4.4
作者：
Bergmann, Sebastian;Funk, Alexander N.;Brakhage, Axel A.
通讯作者：
Brakhage, Axel A.