Introduction
Clinically potent antibacterial drugs are distinguished from antiseptics by their selective toxicity toward the microorganism rather than the host. Selectivity is defined by targeting microbial metabolism or cellular structures that differ from those of mammalian cells. For example, some drugs inhibit the synthesis of bacterial cell walls (which are absent in eukaryotes), while others act on the bacterial ribosome (70S) rather than the eukaryotic ribosome (80S). While penicillin is generally safe for the host, other antibiotics like aminoglycosides require careful dosing and monitoring due to their narrow therapeutic index.
Key Takeaways
- Selective Toxicity: Antibacterial drugs target microbial structures or processes not present in the host.
- Multiple Mechanisms: Antibiotics work through various mechanisms such as inhibiting cell wall synthesis, protein synthesis, or nucleic acid synthesis.
- Resistance Insight: Understanding these mechanisms helps in developing strategies to overcome bacterial resistance.
Antibacterial agents
There are around 23 distinct classes and 18 subclasses of clinically antibacterial drugs, totaling approximately 100 antibiotics. The classification of these antibiotics is complex and continuously evolving. Their mechanisms of action include targeting bacterial cell wall synthesis, folate synthesis, DNA replication, RNA transcription, and mRNA translation. These metabolic processes are sufficiently distinct from those in eukaryotic cells, allowing for selective toxicity. Understanding these mechanisms also provides insights into how microorganisms develop resistance.
- Inhibition of cell wall synthesis
- Inhibition of cell membrane function
- Inhibition of protein synthesis
- Inhibition of nucleic acid synthesis
Inhibition of cell wall synthesis
Many antibacterial drugs work by inhibiting bacterial cell wall synthesis. Mammalian cells lack cell walls, and bacterial cell wall composition varies among species, making this a prime target for antibiotics. The cell wall is composed of a complex polymer called peptidoglycan, which is absent in eukaryotic cells. β-lactam antibiotics, such as penicillins, cephalosporins, carbapenems, and monobactams, inhibit enzymes called penicillin-binding proteins (PBPs) that are crucial for peptidoglycan cross-linking.
Inhibition of cell membrane function
The cytoplasmic membrane in bacteria and fungi acts as a selective permeability barrier and is essential for cell metabolism. Disruption of this membrane causes cell damage or death. Polymyxins, for example, degrade bacterial cell membranes by targeting phosphatidylethanolamine, a key component. Daptomycin depolarizes the bacterial membrane, disrupting its potential and leading to cell death. Amphotericin B, colistin, imidazoles, and triazoles also disrupt cell membrane integrity.
Inhibition of protein synthesis
Protein synthesis in bacteria is targeted by several antibiotics, including macrolides, lincosamides, tetracyclines, glycylcyclines, aminoglycosides, and chloramphenicol. Bacterial cells have 70S ribosomes, whereas mammalian cells have 80S ribosomes. This difference allows selective targeting of bacterial protein synthesis without affecting the host. Aminoglycosides bind to the 30S ribosomal subunit, while tetracyclines prevent amino-acyl-tRNA from attaching to the ribosome. Macrolides and chloramphenicol bind to the 50S subunit, inhibiting peptide bond formation.
Inhibition of nucleic acid synthesis
Quinolones, pyrimethamine, rifampin, sulfonamides, trimethoprim, and trimetrexate inhibit nucleic acid synthesis. Quinolones target DNA gyrase and topoisomerase IV, essential for DNA replication. Sulfonamides and trimethoprim inhibit folate synthesis, crucial for nucleotide biosynthesis. Rifampin binds to RNA polymerase, preventing RNA transcription.
Antibiotic Targets and Pathways
| Drug Type | Drug Name | Species Range | Primary Target | Pathways Affected |
| Fluoroquinolones (DNA Synthesis inhibitor) | Nalidixic Acid, Ciprofloxacin, Ofloxacin, Levofloxacin, Moxifloxacin | Aerobic Gram-positive and gram-negative species, some anaerobic gram-negative species and Mycobacterium | Topoisomerase-II (DNA gyrase) Topoisomerase-IV | DNA replication, SOS response, cell division, ATP generation, TCA cycle, Fe-S cluster synthesis, ROS formation, and envelope and redox-responsive two-component systems |
| Trimethoprim-sulfamethoxazole (DNA synthesis Inhibitor) | Co-Trimoxazole (Combination Of Trimethoprim And Sulfamethoxazole In A 1:5 Ratio) | Aerobic gram-positive and gram-negative species | Tetrahydrofolic acid synthesis inhibitors | Nucleotide biosynthesis and DNA replication |
| Rifamycins (RNA synthesis inhibitors) | Rifamycins, Rifampin, Rifapentine | Gram-positive and gram-negative species and Mycobacteria | DNA-dependent RNA polymerase | RNA transcription, DNA replication and SOS response |
| Beta-Lactams (Cell Wall Synthesis) | Penicillins, Ampicillin, Cephalosporins, Carbapenems | Aerobic and anaerobic gram-positive and gram-negative species | Penicillin-binding proteins. | Cell wall synthesis, cell division, autolysin activity, SOS response, TCA cycle, Fe-S cluster synthesis, ROS formulation and envelope and redox-responsive two component systems |
| Glycopeptides and Glycolipopeptides (Cell wall synthesis inhibitors) | Vancomycin, Teicoplanin | Gram-positive species | Peptidoglycan units (terminal D-Ala-D-Ala dipeptide) | Cell wall synthesis, transglycosylation, transpeptidation, and autolysin activation (VncRS two-component system) |
| Lipopeptides (Cell wall synthesis Inhibitors) | Daptomycin, Polymixin B | Gram-positive species (daptomycin), gram-negative species (polymixins) | Cell membrane | Cell wall synthesis and envelope twocomponent systems |
| Aminoglycosides (Protein synthesis Inhibitors) | Gentamicin, Tobramycin, Streptomycin, Kanamycin | Aerobic gram-positive and gram-negative species, and M. tuberculosis | 30s ribosome | Protein translation (mistranslation by tRNA mismatching), ETC, SOS response, TCA cycle, Fe-S cluster synthesis, ROS formation, and envelope and redox-responsive two-component systems |
| Tetracyclines (Protein synthesis inhibitors) | Tetracycline, Doxycycline | Aerobic gram-positive and gram-negative species | 30s ribosome | Protein translation (through inhibition of aminoacyl-tRNA binding to ribosome) |
| Macrolides (Protein synthesis Inhibitors) | Erythromycin, Azythromycin | Aerobic and anaerobic gram-positive and gram-negative species | 50s ribosome | Protein translation (through inhibition of elongation and translocation steps) and free tRNA depletion |
| Streptogramins (Protein synthesis Inhibitors) | Pristinamycin, Dalfopristin, Quinupristin | Aerobic and anaerobic gram-positive and gram-negative species | 50s ribosome | Protein translation (through inhibition of initiation, elongation, and translocation steps) and free tRNA depletion |
| Phenicols (Protein synthesis Inhibitor) | Chloramphenicol | Some gram-positive and gram-negative species, including B. fragilis, N. meningitidis, H. influenzae, and S. pneumoniae | 50s ribosome | Protein translation (through inhibition of elongation step) |
Conclusion
Understanding the mechanisms of action of antimicrobial agents is crucial for developing effective treatments and combating bacterial resistance. By targeting specific microbial processes and structures, antibiotics can selectively kill or inhibit bacterial growth without harming the host. Continuous research and development in this field are essential for optimizing existing drugs and discovering new ones to keep up with the evolving landscape of bacterial resistance.
FAQs
What is selective toxicity in antibiotics?
Selective toxicity refers to the ability of an antibiotic to target and kill bacterial cells without harming the host’s cells.
How do antibiotics inhibit bacterial cell wall synthesis?
Antibiotics like β-lactams inhibit enzymes involved in peptidoglycan cross-linking, essential for bacterial cell wall strength.
Why are bacterial ribosomes targeted by some antibiotics?
Bacterial ribosomes (70S) are structurally different from eukaryotic ribosomes (80S), allowing antibiotics to selectively inhibit bacterial protein synthesis.
What is the role of quinolones in antibacterial therapy?
Quinolones inhibit DNA gyrase and topoisomerase IV, enzymes crucial for bacterial DNA replication, making them effective antibiotics.
References:
- Textbook of Diagnostic Microbiology 5th Edition. Saunders Elsevier
- Jawetz, Melnick and Adelberg’s Medical Microbiology 26th Edition
- Sherris Medical Microbiology 6th Edition
- Bailey and Scott’s Diagnostic Microbiology 13th Edition