A systematic identification of resistance determinants to antisense antibiotics

The rise of antimicrobial resistance (AMR) among human pathogenic microbes is a serious threat to global health, calling for the development of novel treatment strategies. Antibiotics based on programmable antisense oligomers (asobiotics) offer an attractive solution to the “arms-race”, as their specificity can be quickly updated and tailored to target resistant bacteria. In order to understand the genetic architecture of resistance to asobiotics, we employed laboratory evolution assays to identify mutations that decrease susceptibility to antisense peptide nucleic acid (PNA) against four major gram-negative pathogens: Escherichia coli, Klebsiella pneumoniae, Salmonella enterica, and Pseudomonas aeruginosa.

人类致病微生物的抗菌药物耐药性（antimicrobial resistance, AMR）呈逐年攀升趋势，已对全球健康构成严重威胁，亟需开发新型治疗策略。基于可编程反义寡聚物（programmable antisense oligomers, asobiotics）的抗菌疗法为这场“军备竞赛”提供了极具吸引力的解决方案，因其特异性可快速更新并定制化靶向耐药细菌。为解析针对asobiotics的耐药性遗传结构，我们通过实验室进化实验筛选出可降低对四种主要革兰氏阴性病原菌——大肠杆菌（Escherichia coli）、肺炎克雷伯菌（Klebsiella pneumoniae）、肠炎沙门氏菌（Salmonella enterica）与铜绿假单胞菌（Pseudomonas aeruginosa）——的反义肽核酸（antisense peptide nucleic acid, PNA）敏感性的突变。