Substantial progress has been made in our understanding of the mechanistic details of bacterial cell death induced by bactericidal antibiotics. In this Review, we discuss how bactericidal antibiotics kill bacteria by inhibiting essential cellular processes and by activating cellular response pathways that contribute to cell death.
Bactericidal antibiotics target a diverse set of biomolecules for inhibition to achieve cell death, including DNA topoisomerases (involved in modulating DNA topology), RNA polymerase (involved in RNA transcription), penicillin-binding proteins, transglycosylases and peptidoglycan building blocks (involved in cell wall homeostasis), as well as ribosomes (involved in protein synthesis).
Treatment with lethal concentrations of bactericidal antibiotics has been shown to trigger several stress responses and additional off-target effects in the face of drug-induced stress. These responses include the recently described oxidative damage cellular death pathway, which is commonly induced by all major classes of bactericidal antibiotics and involves alterations in metabolism (that is, central carbon and iron) that culminate in the production of cytotoxic superoxide and hydroxyl radicals.
Several approaches have been employed to provide a more complete understanding of the sequences of events underlying bactericidal antibiotic-induced cell death for each drug class, beginning with the binding of a drug molecule to its primary target. Biological network analysis provides a powerful method for predicting and characterizing the potential interplay between genes and proteins functionally interacting to coordinate bacterial stress response pathways.
Given the threat and continued rise of antibiotic-resistant bacteria, it is crucial that improvements be made to current antibacterial therapies and that new antibiotics are developed. Antibiotic network biology provides a means to comparatively study the response mechanisms of diverse bacterial species to various bactericidal drug classes to predict the responses of pathogenic bacteria to available treatment regimens, and to determine the mode of action of new antibacterial agents.
Antibiotic drug–target interactions, and their respective direct effects, are generally well characterized. By contrast, the bacterial responses to antibiotic drug treatments that contribute to cell death are not as well understood and have proven to be complex as they involve many genetic and biochemical pathways. In this Review, we discuss the multilayered effects of drug–target interactions, including the essential cellular processes that are inhibited by bactericidal antibiotics and the associated cellular response mechanisms that contribute to killing. We also discuss new insights into these mechanisms that have been revealed through the study of biological networks, and describe how these insights, together with related developments in synthetic biology, could be exploited to create new antibacterial therapies.
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We thank the anonymous reviewers for their helpful comments and suggestions. This work was supported by the National Institutes of Health (NIH) through the NIH Director's Pioneer Award Program, grant number DP1 OD003644, and the Howard Hughes Medical Institute.
The authors declare no competing financial interests.
Entrez Genome Project
Antimicrobial exposure that leads to bacterial cell death.
Antimicrobial exposure that inhibits growth with no loss of viability.
- Cell envelope
Layers of the cell surrounding the cytoplasm that include lipid membranes and peptidoglycans.
- SOS response
The DNA stress response pathway in E. coli, the prototypical network of genes of which is regulated by the transcriptional repressor LexA, and is commonly activated by the co-regulatory protein RecA, which promotes LexA self-cleavage when activated.
Rupture of the cell envelope leading to the expulsion of intracellular contents into the surrounding environment with eventual disintegration of the cell envelope.
- Peptidoglycan hydrolase
An enzyme that introduces cuts between carbon–nitrogen non-peptide bonds while pruning the peptidoglycan layer. It is important for homeostatic peptidoglycan turnover.
An enzyme that hydrolyses the β-linkage between the monosaccharide monomers in peptidoglycan units and can induce lysis when in excess.
- Two-component system
A two-protein signal relay system composed of a sensor histidine kinase and a cognate receiver protein, which is typically a transcription factor.
- Quinone pool
Membrane-associated cyclic aromatic-based compounds that shuttle electrons along the electron transport chain.
- Fenton reaction
Reaction of ferrous iron (Fe2+) with hydrogen peroxide to produce ferric iron (Fe3+) and a hydroxyl radical.
- Antimicrobial peptide
A short, naturally occurring cationic peptide that has antibacterial properties through its ability to interfere with bacterial membranes.
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Kohanski, M., Dwyer, D. & Collins, J. How antibiotics kill bacteria: from targets to networks. Nat Rev Microbiol 8, 423–435 (2010). https://doi.org/10.1038/nrmicro2333
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