Luu Irene, Mezcord Vyanka, Escalante Jenny, Traglia German M, Tuttobene Marisel R, Rodriguez Cecilia, Cheng Chun Fu, Valle Quentin, Sharma Rajnikant, Tolmasky Marcelo E, Bonomo Robert A, Rao Gauri, Pasteran Fernando, Ramirez Maria Soledad
Center for Applied Biotechnology Studies, Department of Biological Science, College of Natural Sciences and Mathematics, California State University Fullerton, 800 N State College Blvd, Fullerton, CA 92831, USA.
Unidad de Genómica y Bioinformática, Departamento de Ciencias Biológicas, CENUR Litoral Norte, Universidad de la República, Salto 50000, Uruguay.
Antibiotics (Basel). 2025 Aug 15;14(8):832. doi: 10.3390/antibiotics14080832.
Carbapenem-resistant (CRKP) is an urgent public health threat due to its rapid dissemination and resistance to last-line antibiotics. Cefiderocol (FDC), a novel siderophore cephalosporin, targets resistant Gram-negative pathogens by exploiting bacterial iron uptake mechanisms. However, resistance to FDC is emerging among carbapenemase (KPC)-producing strains. This study characterizes a spontaneous FDC-resistant subpopulation (IHC216) derived from a KPC-producing strain (KPNMA216) using comprehensive genomic, transcriptional, and phenotypic analyses. : Given the whole-genome sequencing results, where mutations were identified in genes involved in transcriptional regulation and membrane permeability () among others, in the present work we further explore their potential implications and conduct a more detailed analysis of the IHC216 genome. A qRT-PCR analysis highlighted significant downregulation of classical siderophore-mediated iron acquisition systems (, , ) and upregulation of alternative iron uptake pathways (, ), reflecting a switch in iron acquisition strategies. : A notable downregulation of correlated with restored susceptibility to carbapenems, indicating collateral susceptibility. Altered expressions of and implicated adaptive changes in cell wall synthesis, potentially affecting FDC resistance mechanisms. Furthermore, enhanced oxidative stress responses via upregulated expression and increased capsule production were observed. : These findings underscore the complex interplay of genetic and transcriptional adaptations underlying FDC resistance, highlighting potential therapeutic vulnerabilities.
耐碳青霉烯类肺炎克雷伯菌（CRKP）因其迅速传播且对一线抗生素耐药，成为紧迫的公共卫生威胁。头孢地尔（FDC）是一种新型的铁载体头孢菌素，它通过利用细菌的铁摄取机制来靶向耐药革兰氏阴性病原体。然而，在产碳青霉烯酶（KPC）的菌株中，对FDC的耐药性正在出现。本研究使用全面的基因组、转录组和表型分析，对一株产KPC菌株（KPNMA216）衍生出的自发FDC耐药亚群（IHC216）进行了表征。鉴于全基因组测序结果，其中在参与转录调控和膜通透性等的基因中发现了突变，在本研究中我们进一步探讨它们的潜在影响，并对IHC216基因组进行更详细的分析。定量逆转录聚合酶链反应（qRT-PCR）分析突出显示经典铁载体介导的铁摄取系统（、、）显著下调，以及替代铁摄取途径（、）上调，这反映了铁摄取策略的转变。与碳青霉烯类药物敏感性恢复相关的显著下调，表明存在协同敏感性。和的表达改变暗示了细胞壁合成中的适应性变化，可能影响FDC耐药机制。此外，观察到通过上调表达增强氧化应激反应以及荚膜产量增加。这些发现强调了FDC耐药背后遗传和转录适应性的复杂相互作用，突出了潜在的治疗弱点。
