Bulman Zackery P, Tan Xing, Chu Ting-Yu, Huang Yanqin, Rana Amisha P, Singh Nidhi, Flowers Stephanie A, Kyono Yasuhiro, Kreiswirth Barry N, Chen Liang
Department of Pharmacy Practice, College of Pharmacy, University of Illinois Chicago, Chicago, IL, USA.
Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, USA.
Comput Struct Biotechnol J. 2022 Jul 15;20:3946-3954. doi: 10.1016/j.csbj.2022.07.017. eCollection 2022.
The combination of carbapenem resistance and hypervirulence in is an emerging and urgent threat due to its potential to resist common antibiotics and cause life-threatening infections in healthy hosts. This study aimed to evaluate the activity of clinically relevant antibiotic regimens against carbapenem-resistant with hypervirulence plasmids and to identify pathways associated with antibiotic tolerance using transcriptomics. We studied two carbapenem-resistant isolates, CDI694 and CDI231, both harboring hypervirulence plasmids. Time-kill and dynamic one-compartment pharmacokinetic/pharmacodynamic assays were used to assess ceftazidime/avibactam-based therapies. RNAseq was performed following 48 h of antibiotic exposure. Closed genomes of CDI694 and CDI231 were obtained; each isolate harbored carbapenem-resistance and hypervirulence (containing and genes) plasmids. Ceftazidime/avibactam-based regimens were bactericidal, though both isolates continued to grow in the presence of antibiotics despite no shifts in MIC. Transcriptomic analyses suggested that perturbations to cell respiration, carbohydrate transport, and stress-response pathways contributed to the antibiotic tolerance in CDI231. Genes associated with hypervirulence and antibiotic resistance were not strongly impacted by drug exposure except for , which was significantly downregulated. Treatment of carbapenem-resistant harboring hypervirulence plasmids with ceftazidime/avibactam-based regimens may yield a tolerant population due to altered transcription of multiple key pathways.
碳青霉烯耐药性与高毒力相结合，因其有可能抵抗常见抗生素并在健康宿主中引起危及生命的感染，正成为一种新出现的紧迫威胁。本研究旨在评估临床相关抗生素方案对携带高毒力质粒的碳青霉烯耐药菌株的活性，并利用转录组学确定与抗生素耐受性相关的途径。我们研究了两株碳青霉烯耐药菌株CDI694和CDI231，它们都携带高毒力质粒。采用时间杀菌和动态单室药代动力学/药效学分析来评估基于头孢他啶/阿维巴坦的治疗方法。在抗生素暴露48小时后进行RNA测序。获得了CDI694和CDI231的封闭基因组；每个菌株都携带碳青霉烯耐药性和高毒力（含有 和 基因）质粒。基于头孢他啶/阿维巴坦的方案具有杀菌作用，尽管两株菌株在抗生素存在的情况下仍继续生长，尽管最低抑菌浓度没有变化。转录组分析表明，细胞呼吸、碳水化合物转运和应激反应途径的扰动导致了CDI231中的抗生素耐受性。除 显著下调外，与高毒力和抗生素耐药性相关的基因受药物暴露的影响不大。用基于头孢他啶/阿维巴坦的方案治疗携带高毒力质粒的碳青霉烯耐药菌株，可能会因多个关键途径的转录改变而产生耐受性群体。
