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Selective toxicity of antibacterial agents-still a valid concept or do we miss chances and ignore risks?
1Christian-Albrechts-University of Kiel, Institue for Infection Medicine, Brunswiker Str. 4, D-24105, Kiel, Germany. adalhoff@t-online.de.
Background:
Selective toxicity antibacteribiotics is considered to be due to interactions with targets either being unique to bacteria or being characterized by a dichotomy between pro- and eukaryotic pathways with high affinities of agents to bacterial- rather than eukaryotic targets. However, the theory of selective toxicity oversimplifies the complex modes of action of antibiotics in pro- and eukaryotes.
Methods And Objective:
This review summarizes data describing multiple modes of action of antibiotics in eukaryotes.
Results:
Aminoglycosides, macrolides, oxazolidinones, chloramphenicol, clindamycin, tetracyclines, glycylcyclines, fluoroquinolones, rifampicin, bedaquillin, ß-lactams inhibited mitochondrial translation either due to binding to mitosomes, inhibition of mitochondrial RNA-polymerase-, topoisomerase 2ß-, ATP-synthesis, transporter activities. Oxazolidinones, tetracyclines, vancomycin, ß-lactams, bacitracin, isoniazid, nitroxoline inhibited matrix-metalloproteinases (MMP) due to chelation with zinc and calcium, whereas fluoroquinols fluoroquinolones and chloramphenicol chelated with these cations, too, but increased MMP activities. MMP-inhibition supported clinical efficacies of ß-lactams and daptomycin in skin-infections, and of macrolides, tetracyclines in respiratory-diseases. Chelation may have contributed to neuroprotection by ß-lactams and fluoroquinolones. Aminoglycosides, macrolides, chloramphenicol, oxazolidins oxazolidinones, tetracyclines caused read-through of premature stop codons. Several additional targets for antibiotics in human cells have been identified like interaction of fluoroquinolones with DNA damage repair in eukaryotes, or inhibition of mucin overproduction by oxazolidinones.
Conclusion:
The effects of antibiotics on eukaryotes are due to identical mechanisms as their antibacterial activities because of structural and functional homologies of pro- and eukaryotic targets, so that the effects of antibiotics on mammals are integral parts of their overall mechanisms of action.
Insights
Antibiotics can harm eukaryotes by targeting similar structures and pathways as in bacteria. This review details multiple antibiotic actions in human cells, revealing shared mechanisms of action.
Area of Science:
- Microbiology
- Molecular Biology
- Pharmacology
Background:
- The traditional view of selective toxicity in antibiotics oversimplifies their complex interactions with both prokaryotic and eukaryotic cells.
- Antibiotics are often thought to target unique bacterial pathways, but this review explores their effects on eukaryotes.
Purpose of the Study:
- To review and summarize the diverse mechanisms by which antibiotics act on eukaryotic cells.
- To highlight the shared targets and pathways between bacterial and eukaryotic cells that antibiotics can affect.
Main Methods:
- Literature review of studies investigating antibiotic mechanisms of action in eukaryotes.
- Analysis of data on antibiotic interactions with eukaryotic cellular components and processes.
Main Results:
- Multiple antibiotic classes, including aminoglycosides, macrolides, and fluoroquinolones, inhibit mitochondrial translation in eukaryotes.
- Antibiotics like oxazolidinones and tetracyclines can inhibit matrix-metalloproteinases (MMPs), influencing clinical efficacy in infections.
- Some antibiotics, such as macrolides and chloramphenicol, can cause read-through of premature stop codons, and others interact with DNA repair pathways.
Conclusions:
- Antibiotic effects on eukaryotes often stem from mechanisms identical to their antibacterial actions due to conserved target structures and functions.
- The observed effects of antibiotics on mammals are integral components of their overall mechanisms of action, not merely off-target effects.
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