Antibiotic intermediates and antibiotics synergistically promote the development of multiple antibiotic resistance in antibiotic production wastewater.

Journal of hazardous materials Pub Date : 2024-11-05 Epub Date: 2024-08-22 DOI:10.1016/j.jhazmat.2024.135601
Sun Miao, Yanyan Zhang, Baochan Li, Xin Yuan, Cong Men, Jiane Zuo
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Abstract

Antibiotic resistance (AR) is a major public health concern. Antibiotic intermediates (AIs) used in the production of semisynthetic antibiotics have the same bioactive structure as parent antibiotics and synthetic antibiotic production wastewater usually contains high concentrations of residual AIs; however, the effects of AIs and their interactive effects with antibiotics on the emergence of AR are unknown. In this study, antibiotic-sensitive E. coli K12 was exposed to five types of β-lactam AIs and their parent antibiotic ampicillin to analyze their impact on the evolution of multiple AR. The results indicated that AI 6-APA inhibits bacterial growth and stimulates the production of reactive oxygen species, as well as induces AR and antibiotic persistence like the parent antibiotic AMP. Combined exposure to 6-APA and AMP synergistically stimulated the induction of multiple AR and antibiotic persistence. The resistance mutation frequency increased up to 6.1 × 106-fold under combined exposure and the combination index reached 1326.5, indicating a strong synergy of 6-APA and AMP. Phenotypic and genotypic analyses revealed that these effects were associated with the overproduction of reactive oxygen species, enhanced stress response signatures, and activation of efflux pumps. These findings provide evidence and mechanistic insights into AR induction by AIs in antibiotic production wastewater.

抗生素中间体和抗生素会协同促进抗生素生产废水中多种抗生素耐药性的产生。
抗生素耐药性(AR)是一个重大的公共卫生问题。用于生产半合成抗生素的抗生素中间体(AIs)具有与母体抗生素相同的生物活性结构,合成抗生素生产废水中通常含有高浓度的残留 AIs;然而,AIs 及其与抗生素的相互作用对 AR 的产生的影响尚不清楚。本研究将对抗生素敏感的大肠杆菌K12暴露于五种β-内酰胺类人工合成物及其母体抗生素氨苄西林中,分析它们对多种AR进化的影响。结果表明,6-APA AI 能抑制细菌生长,刺激活性氧的产生,并能像母体抗生素 AMP 一样诱导 AR 和抗生素持久性。同时接触 6-APA 和 AMP 会协同刺激多种 AR 的诱导和抗生素的持久性。在联合暴露的情况下,耐药性突变频率增加到 6.1 × 106 倍,联合指数达到 1326.5,表明 6-APA 和 AMP 有很强的协同作用。表型和基因型分析表明,这些效应与活性氧的过度产生、应激反应特征的增强以及外排泵的激活有关。这些发现提供了抗生素生产废水中人工合成物诱导 AR 的证据和机理。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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