Molecular Toxicology Group, Department of Plant and Microbial Biology, and Division of Ecosystem Sciences, University of California at Berkeley, Berkeley, California 94720, USA.
Environ Sci Technol. 2010 Feb 15;44(4):1444-50. doi: 10.1021/es902665n.
Recent microcosm studies have revealed that fluoroquinolone (FQ) antibiotics can have ecotoxicological impacts on photosynthetic organisms, but little is known about the mechanisms of toxicity. We employed a combination of modeling and experimental techniques to explore how FQs may have these unintended secondary toxic effects. Structure-activity analysis revealed that the quinolone ring and secondary amino group typically present in FQ antibiotics may mediate their action as quinone site inhibitors in photosystem II (PS-II), a key enzyme in photosynthetic electron transport. Follow-up molecular simulations involving nalidixic acid (Naldx), a nonfluorinated quinolone with a demonstrated adverse impact on photosynthesis, and ciprofloxacin (Cipro), the most commonly used FQ antibiotic, showed that both may interfere stereochemically with the catalytic activity of reaction center II (RC-II), the pheophytin-quinone-type center present in PS-II. Naldx can occupy the same binding site as the secondary quinone acceptor (Q(B)) in RC-II and interact with amino acid residues required for the enzymatic reduction of Q(B). Cipro binds in a somewhat different manner, suggesting a different mechanism of interference. Fluorescence induction kinetics, a common method of screening for PS-II inhibition, recorded for photoexcited thylakoid membranes isolated from Cipro-exposed spinach chloroplasts, indicated that Cipro interferes with the transfer of energy from excited antenna chlorophyll molecules to the reaction center in RC-II ([Cipro] >or= 5 microM in vitro and >or=10 microM in vivo) and thus delays the kinetics of photoreduction of the primary quinone acceptor (Q(A); [Cipro] >or= 0.6 microM in vitro). Spinach plants exposed to Cipro exhibited severe growth inhibition characterized by a decrease in both the synthesis of leaves and growth of the roots ([Cipro] >or= 0.5 microM in vivo). Our results thus demonstrate that Cipro and related FQ antibiotics may interfere with photosynthetic pathways, in addition to causing morphological deformities in higher plants.
最近的微观研究揭示，氟喹诺酮（FQ）抗生素对光合生物具有生态毒理学影响，但毒性机制知之甚少。我们采用建模和实验技术相结合的方法，探讨 FQ 如何产生这些非预期的次级毒性作用。结构-活性分析表明，喹诺酮环和 FQ 抗生素中通常存在的二级氨基基团可能介导其作为光合系统 II（PS-II）醌结合位点抑制剂的作用，PS-II 是光合作用电子传递中的关键酶。随后涉及萘啶酸（Naldx）和环丙沙星（Cipro）的分子模拟实验，Naldx 是一种具有不良光合作用影响的非氟喹诺酮，Cipro 是最常用的 FQ 抗生素，结果表明，这两种药物都可能在立体化学上干扰反应中心 II（RC-II）的催化活性，RC-II 是 PS-II 中存在的叶绿素醌型中心。Naldx 可以占据 RC-II 中与次级醌受体（Q(B)）相同的结合位点，并与酶促还原 Q(B)所需的氨基酸残基相互作用。Cipro 以略有不同的方式结合，表明存在不同的干扰机制。荧光诱导动力学是筛选 PS-II 抑制的常用方法，用该方法记录从暴露于 Cipro 的菠菜叶绿体中分离出的光激发类囊体膜的动力学，结果表明 Cipro 干扰了从激发天线叶绿素分子到 RC-II 中反应中心的能量转移([Cipro] >or= 5 microM 在体外，>or=10 microM 在体内)，从而延迟了初级醌受体（Q(A)）的光还原动力学([Cipro] >or= 0.6 microM 在体外)。暴露于 Cipro 的菠菜植物表现出严重的生长抑制，表现为叶片合成和根生长均减少([Cipro] >or= 0.5 microM 在体内)。因此，我们的结果表明，Cipro 和相关的 FQ 抗生素可能除了引起高等植物形态畸形外，还可能干扰光合作用途径。
