Yang Xiaohan, Chu Jinhua, Huang Lulu, Farhan Muhammad Haris Raza, Feng Mengyao, Bai Jiapeng, Wang Bangjuan, Cheng Guyue
National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan 430070, China.
MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan 430070, China.
Antibiotics (Basel). 2025 Jul 29;14(8):767. doi: 10.3390/antibiotics14080767.
infections pose a serious threat to both animal and human health worldwide. Notably, there is an increasing trend in the resistance of to fluoroquinolones, the first-line drugs for clinical treatment.
Utilizing Typhimurium CICC 10420 as the test strain, ciprofloxacin was used for in vitro induction to develop the drug-resistant strain H1. Changes in the minimum inhibitory concentrations (MICs) of various antimicrobial agents were determined using the broth microdilution method. Transcriptomic and metabolomic analyses were conducted to investigate alterations in gene and metabolite expression. A combined drug susceptibility test was performed to evaluate the potential of exogenous metabolites to restore antibiotic susceptibility.
The MICs of strain H1 for ofloxacin and enrofloxacin increased by 128- and 256-fold, respectively, and the strain also exhibited resistance to ceftriaxone, ampicillin, and tetracycline. A single-point mutation of Glu469Asp in the GyrB was detected in strain H1. Integrated multi-omics analysis showed significant differences in gene and metabolite expression across multiple pathways, including two-component systems, ABC transporters, pentose phosphate pathway, purine metabolism, glyoxylate and dicarboxylate metabolism, amino sugar and nucleotide sugar metabolism, pantothenate and coenzyme A biosynthesis, pyrimidine metabolism, arginine and proline biosynthesis, and glutathione metabolism. Notably, the addition of exogenous glutamine, in combination with tetracycline, significantly reduced the resistance of strain H1 to tetracycline.
Ciprofloxacin-induced resistance involves both target site mutations and extensive reprogramming of the metabolic network. Exogenous metabolite supplementation presents a promising strategy for reversing resistance and enhancing antibiotic efficacy.
感染对全球动物和人类健康构成严重威胁。值得注意的是，临床治疗的一线药物氟喹诺酮类药物的耐药性呈上升趋势。
以鼠伤寒沙门氏菌CICC 10420为测试菌株，用环丙沙星进行体外诱导以构建耐药菌株H1。采用肉汤微量稀释法测定各种抗菌药物的最低抑菌浓度（MIC）变化。进行转录组学和代谢组学分析以研究基因和代谢物表达的变化。进行联合药敏试验以评估外源性代谢物恢复抗生素敏感性的潜力。
菌株H1对氧氟沙星和恩诺沙星的MIC分别增加了128倍和256倍，该菌株还对头孢曲松、氨苄青霉素和四环素表现出耐药性。在菌株H1中检测到GyrB基因的Glu469Asp单点突变。综合多组学分析表明，多个途径的基因和代谢物表达存在显著差异，包括双组分系统、ABC转运蛋白、磷酸戊糖途径、嘌呤代谢、乙醛酸和二羧酸代谢、氨基糖和核苷酸糖代谢、泛酸和辅酶A生物合成、嘧啶代谢、精氨酸和脯氨酸生物合成以及谷胱甘肽代谢。值得注意的是，添加外源性谷氨酰胺并联合四环素可显著降低菌株H1对四环素的耐药性。
环丙沙星诱导的耐药性涉及靶点突变和代谢网络的广泛重编程。补充外源性代谢物是一种有前景的逆转耐药性和提高抗生素疗效的策略。
