Kalu Michelle Chioma, Acharya Akanksha, Jorth Peter, Wong-Beringer Annie
Titus Family Department of Clinical Pharmacy, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90033, USA.
Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Microorganisms. 2025 Jun 14;13(6):1387. doi: 10.3390/microorganisms13061387.
Treatment of infections caused by ESBL-producing (EC) and (KP) with carbapenem antibiotics can lead to the development of carbapenem resistance over time through the acquisition of porin mutations and plasmids bearing . However, the impact of genetic background and the presence of CRISPR-Cas systems on the evolutionary path towards carbapenem resistance in EC and KP has yet to be investigated. The in-human evolution following repeated carbapenem treatment among ESBL-producing (EC) and (KP) clinical pairs (n = 45 pairs) was examined to determine the relationship between strain genetic background (MLST, CRISPR-Cas) and the evolved genetic mutations related to resistance, virulence, and metabolism by whole genome sequencing. ST131 and ST258 were predominant among seven distinct STs in EC (70%, 19/27) and 11 STs in KP (33%, 6/18), respectively. Complete CRISPR-Cas systems were present in 22% EC (6/27) and 27.8% (5/18) KP pairs, but none in strains belonging to ST131 or ST258; partial loss of CRISPR-Cas was associated with increased carbapenem resistance. Porin, virulence, and metabolism-related genetic mutations were present on the chromosome in both the EC and KP evolved strains, but their presence was differentially associated with the CRISPR-Cas system. Future research on the role of antibiotic exposure in the species-specific resistance evolution of the could guide antimicrobial stewardship efforts.
使用碳青霉烯类抗生素治疗产超广谱β-内酰胺酶（ESBL）的大肠埃希菌（EC）和肺炎克雷伯菌（KP）引起的感染，随着时间的推移，通过获得孔蛋白突变和携带 blaKPC 的质粒，可能会导致碳青霉烯类耐药性的产生。然而，遗传背景和 CRISPR-Cas 系统的存在对 EC 和 KP 向碳青霉烯类耐药性进化途径的影响尚未得到研究。通过全基因组测序，研究了产 ESBL 的 EC 和 KP 临床配对菌株（n = 45 对）在反复碳青霉烯治疗后的人体进化情况，以确定菌株遗传背景（多位点序列分型、CRISPR-Cas）与耐药性、毒力和代谢相关的进化基因突变之间的关系。ST131 和 ST258 分别在 EC 的 7 种不同序列型中占主导地位（70%，19/27），在 KP 的 11 种序列型中占主导地位（33%，6/18）。22%的 EC 配对菌株（6/27）和 27.8%的 KP 配对菌株（5/18）存在完整的 CRISPR-Cas 系统，但属于 ST131 或 ST258 的菌株中均无完整系统；CRISPR-Cas 的部分缺失与碳青霉烯类耐药性增加有关。EC 和 KP 进化菌株的染色体上均存在孔蛋白、毒力和代谢相关的基因突变，但其存在与 CRISPR-Cas 系统的相关性存在差异。未来关于抗生素暴露在该菌属特异性耐药性进化中作用的研究，可为抗菌药物管理工作提供指导。
