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How antibiotics kill bacteria: from targets to networks.
Literature Information
| DOI | 10.1038/nrmicro2333 |
|---|---|
| PMID | 20440275 |
| Journal | Nature reviews. Microbiology |
| Impact Factor | 103.3 |
| JCR Quartile | Q1 |
| Publication Year | 2010 |
| Times Cited | 769 |
| Keywords | Antibiotics, Bacterial Death, Drug Targets, Biological Networks, Synthetic Biology |
| Literature Type | Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review |
| ISSN | 1740-1526 |
| Pages | 423-35 |
| Issue | 8(6) |
| Authors | Michael A Kohanski, Daniel J Dwyer, James J Collins |
TL;DR
This review examines the complex bacterial responses to antibiotic treatments that lead to cell death, highlighting the inhibition of essential cellular processes by bactericidal antibiotics and the associated response mechanisms. The findings underscore the potential to leverage insights from biological networks and synthetic biology to develop novel antibacterial therapies.
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Antibiotics · Bacterial Death · Drug Targets · Biological Networks · Synthetic Biology
Abstract
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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Primary Questions Addressed
- What are the specific genetic and biochemical pathways involved in bacterial responses to antibiotic treatments?
- How do different classes of antibiotics vary in their mechanisms of action and effects on bacterial cell death?
- In what ways can synthetic biology contribute to the development of new antibacterial therapies based on our understanding of drug-target interactions?
- What role do biological networks play in the cellular response mechanisms that contribute to the efficacy of bactericidal antibiotics?
- How can insights from the study of antibiotic drug-target interactions inform strategies to combat antibiotic resistance?
Key Findings
Research Background and Purpose
The review discusses the complex mechanisms by which antibiotics induce bacterial cell death. While the interactions between antibiotics and their targets are well understood, the bacterial responses that lead to cell death are less clear. This review aims to explore the multifaceted effects of drug-target interactions and the cellular response mechanisms involved in antibiotic-induced cell death. Additionally, it seeks to identify how insights from biological networks and synthetic biology can be leveraged to develop new antibacterial therapies.
Main Methods/Materials/Experimental Design
The authors utilized a combination of biochemical analysis, genetic screening, and network biology approaches to investigate the effects of various classes of antibiotics on bacterial cells. The following key methods were employed:
- Antibiotic Classification: Antibiotics were classified based on their primary targets (e.g., DNA, RNA, cell wall, and protein synthesis) and their effects (bactericidal vs. bacteriostatic).
- Network Biology: High-throughput genetic screening and gene expression profiling were used to analyze bacterial responses to antibiotic treatments.
- Mechanistic Studies: Detailed mechanistic insights were derived from studying how different antibiotics induce cellular stress responses, leading to cell death.
Key Results and Findings
- Common Mechanism of Cell Death: All major classes of bactericidal antibiotics induce a common mechanism of cell death characterized by the production of reactive oxygen species (ROS) and oxidative damage.
- Drug-Target Interactions: Specific interactions include:
- Quinolones: Induce double-stranded DNA breaks by inhibiting topoisomerase.
- Rifamycins: Inhibit RNA synthesis by binding to RNA polymerase.
- β-lactams: Inhibit cell wall synthesis by targeting penicillin-binding proteins (PBPs).
- Aminoglycosides: Cause protein mistranslation and disrupt ribosomal function.
- Role of SOS Response: The SOS response pathway is activated in response to DNA damage, which can influence the effectiveness of antibiotic treatments and the development of resistance.
Main Conclusions/Significance/Innovativeness
The review highlights the complexity of antibiotic-induced cell death and the need for a deeper understanding of bacterial stress responses. The identification of common oxidative damage pathways suggests potential targets for enhancing the efficacy of existing antibiotics and developing new therapies. Furthermore, the integration of synthetic biology with antibiotic research offers innovative approaches to combat antibiotic resistance.
Research Limitations and Future Directions
- Limitations: The review acknowledges that while significant insights have been gained, the exact mechanisms of how various antibiotics induce cell death remain partially understood. The variability in bacterial responses to antibiotics complicates the generalization of findings.
- Future Directions: Future research should focus on:
- Elucidating the specific molecular pathways involved in antibiotic-induced cell death.
- Exploring the interplay between different stress response networks in various bacterial species.
- Developing synthetic biology tools to manipulate bacterial responses to antibiotics, potentially leading to novel therapeutic strategies.
Summary Table of Antibiotic Classes and Mechanisms
| Antibiotic Class | Primary Target | Mechanism of Action | Effects on Bacteria |
|---|---|---|---|
| Quinolones | Topoisomerase | Induces DNA breaks | Cell death via oxidative damage |
| Rifamycins | RNA Polymerase | Inhibits RNA synthesis | Cell death via transcription disruption |
| β-lactams | Penicillin-binding proteins | Inhibits cell wall synthesis | Cell lysis and death |
| Aminoglycosides | Ribosome | Causes mistranslation of proteins | Increased permeability and cell death |
This structured summary encapsulates the review's key points, providing a comprehensive overview of antibiotic mechanisms, cellular responses, and future research avenues in the context of bacterial cell death.
References
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Literatures Citing This Work
- Insights into an unusual nonribosomal peptide synthetase biosynthesis: identification and characterization of the GE81112 biosynthetic gene cluster. - Tina M Binz;Sonia I Maffioli;Margherita Sosio;Stefano Donadio;Rolf Müller - The Journal of biological chemistry (2010)
- The future of the β-lactams. - Leticia I Llarrull;Sebastian A Testero;Jed F Fisher;Shahriar Mobashery - Current opinion in microbiology (2010)
- Emergence of Pseudomonas aeruginosa strains producing high levels of persister cells in patients with cystic fibrosis. - Lawrence R Mulcahy;Jane L Burns;Stephen Lory;Kim Lewis - Journal of bacteriology (2010)
- Conflicts targeting epigenetic systems and their resolution by cell death: novel concepts for methyl-specific and other restriction systems. - Ken Ishikawa;Eri Fukuda;Ichizo Kobayashi - DNA research : an international journal for rapid publication of reports on genes and genomes (2010)
- An incomplete TCA cycle increases survival of Salmonella Typhimurium during infection of resting and activated murine macrophages. - Steven D Bowden;Vinoy K Ramachandran;Gitte M Knudsen;Jay C D Hinton;Arthur Thompson - PloS one (2010)
- Identification of a chemical that inhibits the mycobacterial UvrABC complex in nucleotide excision repair. - Nayef Mazloum;Melanie A Stegman;Deborah L Croteau;Bennett Van Houten;Nyoun Soo Kwon;Yan Ling;Caitlyn Dickinson;Aditya Venugopal;Mohammad Atif Towheed;Carl Nathan - Biochemistry (2011)
- Depletion of antibiotic targets has widely varying effects on growth. - Jun-Rong Wei;Vidhya Krishnamoorthy;Kenan Murphy;Jee-Hyun Kim;Dirk Schnappinger;Tom Alber;Christopher M Sassetti;Kyu Y Rhee;Eric J Rubin - Proceedings of the National Academy of Sciences of the United States of America (2011)
- Drug tolerance in replicating mycobacteria mediated by a macrophage-induced efflux mechanism. - Kristin N Adams;Kevin Takaki;Lynn E Connolly;Heather Wiedenhoft;Kathryn Winglee;Olivier Humbert;Paul H Edelstein;Christine L Cosma;Lalita Ramakrishnan - Cell (2011)
- Glutathione facilitates antibiotic resistance and photosystem I stability during exposure to gentamicin in cyanobacteria. - Jeffrey C Cameron;Himadri B Pakrasi - Applied and environmental microbiology (2011)
- Molecular recognition of chymotrypsin by the serine protease inhibitor ecotin from Yersinia pestis. - Elizabeth A Clark;Nicola Walker;Donna C Ford;Ian A Cooper;Petra C F Oyston;K Ravi Acharya - The Journal of biological chemistry (2011)
... (759 more literatures)
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