Low-Level Cefepime Exposure Induces High-Level Resistance in Environmental Bacteria: Molecular Mechanism and Evolutionary Dynamics,Environmental Science & Technology

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Low-Level Cefepime Exposure Induces High-Level Resistance in Environmental Bacteria: Molecular Mechanism and Evolutionary Dynamics
Environmental Science & Technology ( IF 10.8 ) Pub Date : 2022-05-24 , DOI: 10.1021/acs.est.2c00793
Hanqing Wang ₁ , Youjun Feng ₂ , Huijie Lu _{1,

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Affiliation

Antibiotics exert selective pressures on clinically relevant antibiotic resistance. It is critical to understand how antibiotic resistance evolves in environmental microbes exposed to subinhibitory concentrations of antibiotics and whether evolutionary dynamics and emergence of resistance are predictable. In this study, Comamonas testosteroni isolated from wastewater activated sludge were subcultured in a medium containing 10 ng/mL cefepime for 40 days (∼300 generations). Stepwise mutations were accumulated, leading to an ultimate 200-fold increase in the minimum inhibitory concentration (MIC) of cefepime. Early stage mutation in DNA polymerase-encoding gene dnaE2 played an important role in antibiotic resistance evolution. Diverse resistance mechanisms were employed and validated experimentally, including increased efflux, biofilm formation, reduced antibiotic uptake, and drug inactivation. The cefepime minimal selective concentrations (MSCs) and relative fitness of susceptible, intermediate, and resistant mutants were determined. Agent-based modeling of the modified Moran process enabled simulations of resistance evolution and predictions of the emergence time and frequency of resistant mutants. The unraveled cefepime resistance mechanisms could be employed by broader bacteria, and the newly developed model is applicable to the predictions of general resistance evolution. The improved knowledge facilitates the assessment, prediction, and mitigation of antibiotic resistance progression in antibiotic-polluted environments.

中文翻译：

低水平头孢吡肟暴露诱导环境细菌的高水平耐药性：分子机制和进化动力学

抗生素对临床相关的抗生素耐药性施加选择性压力。了解暴露于亚抑制浓度抗生素的环境微生物中抗生素耐药性如何演变以及进化动力学和耐药性的出现是否可预测是至关重要的。在这项研究中，从废水活性污泥中分离出的睾丸毛单胞菌在含有 10 ng/mL 头孢吡肟的培养基中传代培养 40 天（约 300 代）。逐步突变被积累，导致头孢吡肟的最小抑制浓度 (MIC) 最终增加 200 倍。DNA聚合酶编码基因dnaE2的早期突变在抗生素耐药性的进化中发挥了重要作用。采用了多种耐药机制并通过实验验证，包括外排增加、生物膜形成、抗生素摄取减少和药物失活。确定了头孢吡肟最小选择性浓度 (MSC) 和易感、中间和抗性突变体的相对适应性。修改后的莫兰过程的基于代理的建模能够模拟抗性进化和预测抗性突变体的出现时间和频率。已阐明的头孢吡肟抗性机制可用于更广泛的细菌，新开发的模型适用于一般抗性进化的预测。改进的知识有助于评估、预测、

更新日期：2022-05-24

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