Sadek Mustafa, Duran Juan Bosch, Chakraborty Trinad, Poirel Laurent, Nordmann Patrice
Medical and Molecular Microbiology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland.
Department of Food Hygiene and Control, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt.
Eur J Clin Microbiol Infect Dis. 2025 May 27. doi: 10.1007/s10096-025-05166-w.
A series of NDM-producing Escherichia coli ST167 clinical isolates exhibiting resistance to cefiderocol (FDC), with no previous exposure to this antibiotic, were analyzed in this study.
The antimicrobial susceptibility testing and phenotypic detection of resistance patterns (Rapid Cefiderocol NP test and MIC determination) were performed for all tested isolates. Their entire genomes were sequenced by using the Illumina MiSeq platform and high-quality reads were de-novo assembled using the CLC Genomic Workbench. Genome-sequence based characteristics were analyzed using bioinformatics tools.
All NDM-producing E. coli ST167 isolates showed a high level of resistance to FDC (MICs being 64 or > 64 mg/L). The chromosomally located cirA gene, encoding a catecholate siderophore receptor in E. coli, was truncated in all FDC-resistant isolates due to a frameshift mutation (S90Y), leading to CirA-deficient isolates. A four amino acid insertion (YRIN) was also identified after residue 333 in the PBP3 protein sequence of all E. coli isolates. Among them, a single FDC-resistant NDM-5-producing E. coli isolate (1006) was additionally resistant to aztreonam/avibactam (AZA MIC of 8 mg/L). When analyzed against the genome of another FDC resistant NDM-5 producing E. coli ST167 containing a YRIN insertion in the PBP3, and exhibiting decreased susceptibility to AZA, the broad-spectrum ß-lactamase CMY-42 was identified.
We identified a variety of NDM-producing E. coli isolates exhibiting high level of resistance to FDC as a result of the combined effect of CirA deficiency, along with production of NDM-type enzymes. The spread of such resistance phenotype across Europe poses great concern on the clinical efficacy of this novel drug. Additionally, the identification of an FDC- and AZA-resistant NDM-5 producing E. coli isolate represents one of the ultimate evolutions with a possible step towards pan-resistance.
本研究分析了一系列产NDM的大肠埃希菌ST167临床分离株，这些分离株对头孢地尔（FDC）耐药，且此前未接触过这种抗生素。
对所有测试分离株进行抗菌药物敏感性试验和耐药模式的表型检测（快速头孢地尔NP试验和MIC测定）。使用Illumina MiSeq平台对它们的全基因组进行测序，并使用CLC Genomic Workbench对高质量读段进行从头组装。使用生物信息学工具分析基于基因组序列的特征。
所有产NDM的大肠埃希菌ST167分离株对FDC均表现出高水平耐药（MIC为64或>64 mg/L）。在所有耐FDC的分离株中，位于染色体上的cirA基因（编码大肠埃希菌中的儿茶酚盐铁载体受体）由于移码突变（S90Y）而被截断，导致CirA缺陷型分离株。在所有大肠埃希菌分离株的PBP3蛋白序列中，第333位残基后还鉴定出一个四氨基酸插入（YRIN）。其中，一株耐FDC的产NDM-5大肠埃希菌分离株（1006）对氨曲南/阿维巴坦也耐药（AZA MIC为8 mg/L）。当与另一株耐FDC的产NDM-5大肠埃希菌ST167的基因组进行比对分析时，该菌株在PBP3中含有YRIN插入，且对AZA的敏感性降低，鉴定出了广谱β-内酰胺酶CMY-42。
我们鉴定出多种产NDM的大肠埃希菌分离株，由于CirA缺陷与NDM型酶产生的联合作用，这些分离株对FDC表现出高水平耐药。这种耐药表型在欧洲的传播对这种新型药物的临床疗效构成了极大担忧。此外，鉴定出一株耐FDC和AZA的产NDM-5大肠埃希菌分离株代表了最终的进化之一，可能朝着泛耐药迈出了一步。
