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Phagomimetic action of antimicrobial agents
J M Gutteridge1, G J Quinlan, P Kovacic
1Oxygen Chemistry Laboratory, Unit of Critical Care, Royal Brompton Hospital, London, UK.
Abstract:
A wide variety of extracted and synthesised drug molecules have electron transfer capabilities which allow them to generate reactive oxygen species (ROS). In particular, many antibiotics that kill or inhibit bacteria, yeasts and cancer cells readily transfer electrons to oxygen making superoxide and hydrogen peroxide in the process. When suitable redox active forms of iron are available, Fenton chemistry occurs generating the highly damaging hydroxyl radical. This type of chemistry is very similar to that which evolved within phagocytic cells as part of their microbial killing armoury. Many antibiotics, when used in model systems, have well defined pharmacological actions against key cellular functions, but their clinical usefulness is also often demonstrable at concentrations in vivo well below their in vitro minimum inhibitory concentrations. These observations have led us to propose that a common mechanism exists whereby phagocytic cells and antibiotics exploit the use of ROS for microbial killing.
Insights
Many drugs generate reactive oxygen species (ROS), like antibiotics, which can kill microbes. This mechanism, involving ROS and iron, mirrors natural microbial defenses in phagocytic cells.
Area of Science:
- Biochemistry
- Microbiology
- Pharmacology
Background:
- Many drug molecules, including antibiotics, possess electron transfer capabilities.
- These molecules can generate reactive oxygen species (ROS) by transferring electrons to oxygen, producing superoxide and hydrogen peroxide.
- In the presence of redox-active iron, Fenton chemistry generates highly damaging hydroxyl radicals.
Purpose of the Study:
- To propose a common mechanism for microbial killing utilized by both phagocytic cells and antibiotics.
- To explore the role of reactive oxygen species (ROS) in antibiotic-mediated microbial inhibition.
- To investigate the similarity between the evolved microbial killing mechanisms in phagocytic cells and the chemical actions of certain drugs.
Main Methods:
- Review of existing literature on drug molecule redox capabilities and ROS generation.
- Analysis of antibiotic mechanisms of action against bacteria, yeasts, and cancer cells.
- Comparison of ROS-generating chemistry in vitro with biological processes in phagocytic cells.
Main Results:
- Numerous antibiotics readily generate ROS, contributing to their antimicrobial and anticancer effects.
- The ROS-generating chemistry of antibiotics closely resembles the oxidative stress mechanisms employed by phagocytic immune cells.
- Antibiotics demonstrate significant in vivo efficacy at concentrations below their in vitro minimum inhibitory concentrations, suggesting non-traditional mechanisms.
Conclusions:
- A shared mechanism involving ROS exploitation for microbial killing exists between phagocytic cells and certain antibiotics.
- Antibiotics may leverage oxidative stress pathways, similar to innate immunity, to achieve therapeutic effects.
- Understanding this common mechanism could lead to novel therapeutic strategies targeting microbial infections and cancer.