Inhibition of photosynthesis by a fluoroquinolone antibiotic.
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.
Aristilde
Ludmilla
L
Molecular Toxicology Group, Department of Plant and Microbial Biology, and Division of Ecosystem Sciences, University of California at Berkeley, Berkeley, California 94720, USA. ludmilla@princeton.edu
Melis
Anastasios
A
Sposito
Garrison
G
D000900:Anti-Bacterial Agents / Q000633:toxicity*; D002939:Ciprofloxacin / Q000633:toxicity; D024841:Fluoroquinolones / Q000633:toxicity*; D015394:Molecular Structure; D009268:Nalidixic Acid / Q000633:toxicity; D010788:Photosynthesis / Q000187:drug effects*; D018724:Spinacia oleracea / Q000187:drug effects / Q000378:metabolism
D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D009268:Nalidixic Acid; D002939:Ciprofloxacin