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DNA base damage by beta-lactam, tetracycline, bacitracin and rifamycin antibacterial antibiotics
1Department of Anaesthesia and Intensive Care, Royal Brompton Hospital, London, U.K.
Abstract:
Several antibacterial antibiotics have been shown to participate with transition metal ions in chemical reactions leading to the formation of reactive oxygen species. An important host defence mechanism for dealing with invading bacteria involves the production of reactive oxygen species, such as superoxide, hydrogen peroxide and hypochlorous acid, by phagocytic cells. The production of reactive oxygens by redox cycling antibacterial antibiotics has led us to suggest that a 'phagomimetic' contribution may also be made in vivo. Here we show that four structurally different antibacterial antibiotics, in the presence of added copper salt, bring about oxidative modification to bases in DNA detected using gas chromatography-mass spectrometry. The drug most damaging to DNA was rifamycin SV which was more active than a reference mixture of hydrogen peroxide and ascorbic acid.
Insights
Antibacterial antibiotics and copper can generate harmful reactive oxygen species, damaging bacterial DNA. Rifamycin SV demonstrated the most significant DNA damage, exceeding hydrogen peroxide and ascorbic acid effects.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Antibacterial antibiotics interact with transition metal ions, producing reactive oxygen species (ROS).
- Phagocytic cells use ROS as a host defense mechanism against bacteria.
- Antibiotic-induced ROS production may mimic host defense responses in vivo.
Purpose of the Study:
- To investigate the potential of antibacterial antibiotics to induce DNA damage via ROS formation.
- To assess the DNA-damaging activity of different antibiotics in the presence of copper.
- To compare the efficacy of antibiotic-induced DNA damage with known ROS agents.
Main Methods:
- Exposure of DNA to four different antibacterial antibiotics and copper salt.
- Detection and quantification of oxidative DNA base modifications using gas chromatography-mass spectrometry.
- Comparison with DNA damage induced by hydrogen peroxide and ascorbic acid.
Main Results:
- Four tested antibiotics, with copper, induced oxidative modifications in DNA bases.
- Rifamycin SV exhibited the highest DNA-damaging activity among the tested antibiotics.
- Rifamycin SV's DNA-damaging effect was more potent than a mixture of hydrogen peroxide and ascorbic acid.
Conclusions:
- Certain antibacterial antibiotics can cause DNA damage through ROS generation in the presence of copper.
- This mechanism suggests a potential 'phagomimetic' role for these antibiotics in vivo.
- Rifamycin SV is a potent inducer of antibiotic-mediated DNA damage.