研究基于CRISPR的抗菌剂的CRISPR-Cas基因组的基因组背景
Investigating the genomic background of CRISPR-Cas genomes for CRISPR-based antimicrobials
摘要：
CRISPR-Cas系统是一种适应性免疫，可保护原核生物免受外来遗传因子的影响。在过去的感染事件中获得的遗传模板使DNA相互作用酶能够识别外来DNA并进行破坏。由于这些遗传模板的可编程性和特异性，CRISPR-Cas系统是潜在的替代抗生素，可以被工程化以自靶向染色体或质粒上的抗微生物剂抗性基因。然而，一些基本问题仍然存在，以重新利用这些工具来对抗耐药细菌。对于内源性CRISPR-Cas自我靶向，抗微生物剂抗性基因和功能性CRISPR-Cas系统必须在靶细胞中共存。此外，这些工具必须胜过响应Cas蛋白的核酸酶活性的DNA修复途径，即使对于外源性CRISPR-Cas递送也是如此。在这里，我们对CRISPR-Cas基因组进行了全面的调查。首先，我们解决了CRISPR-Cas系统和CRISPR-Cas基因组中抗菌素耐药基因的共同出现。我们发现这些基因的平均数量因CRISPR-Cas类型而异，一些CRISPR-Cas类型（IE和IIIA）每个基因组有超过20个基因。接下来，我们研究了这些CRISPR-Cas基因组的DNA修复途径，揭示了这些途径的多样性和频率因CRISPR-Cas类型而异。CRISPR-Cas系统和DNA修复途径之间的相互作用对于在CRISPR阵列中获得新的间隔区至关重要。我们进行模拟研究，以证明这些DNA修复途径的效率可以从CRISPR重复序列的RNA结构中的时间序列模式推断出来。这项对CRISPR-Cas基因组的生物信息学调查阐明了考虑不同基因和系统之间多方面相互作用以设计有效的基于CRISPR的抗菌剂的必要性。
英文摘要：
CRISPR-Cas systems are an adaptive immunity that protects prokaryotes against foreign genetic elements. Genetic templates acquired during past infection events enable DNA-interacting enzymes to recognize foreign DNA for destruction. Due to the programmability and specificity of these genetic templates, CRISPR-Cas systems are potential alternative antibiotics that can be engineered to self-target antimicrobial resistance genes on the chromosome or plasmid. However, several fundamental questions remain to repurpose these tools against drug-resistant bacteria. For endogenous CRISPR-Cas self-targeting, antimicrobial resistance genes and functional CRISPR-Cas systems have to co-occur in the target cell. Furthermore, these tools have to outplay DNA repair pathways that respond to the nuclease activities of Cas proteins, even for exogenous CRISPR-Cas delivery. Here, we conduct a comprehensive survey of CRISPR-Cas genomes. First, we address the co-occurrence of CRISPR-Cas systems and antimicrobial resistance genes in the CRISPR-Cas genomes. We show that the average number of these genes varies greatly by the CRISPR-Cas type, and some CRISPR-Cas types (IE and IIIA) have over 20 genes per genome. Next, we investigate the DNA repair pathways of these CRISPR-Cas genomes, revealing that the diversity and frequency of these pathways differ by the CRISPR-Cas type. The interplay between CRISPR-Cas systems and DNA repair pathways is essential for the acquisition of new spacers in CRISPR arrays. We conduct simulation studies to demonstrate that the efficiency of these DNA repair pathways may be inferred from the time-series patterns in the RNA structure of CRISPR repeats. This bioinformatic survey of CRISPR-Cas genomes elucidates the necessity to consider multifaceted interactions between different genes and systems to design effective CRISPR-based antimicrobials.
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