The term antibiotics have been derived from the word antibiosis, which means ‘against life.’ Antibiotics are organic compounds produced by one microorganism, which are toxic to other microorganisms even at low concentrations. However, modern antibiotics are also made partly or wholly through synthetic means. Antibiotics inhibit or kill microorganisms, more specifically bacteria, through various mechanisms acting on different cell sites. The mechanism of action of antibiotics varies broadly.
Classification Schemes of Antibiotics
There are many ways to classify antibiotics. Most common schemes are based on their molecular structures, mode of action, and spectrum of activity. Antibiotics of the same structure show similar effectiveness and toxicity.
Standard classes of antibiotics based on structure include Beta-lactams, Macrolides, Tetracyclines, Quinolones, Aminoglycosides, Sulphonamides, Glycopeptides, and Oxazolidones.
Mechanisms of Action of Antibiotics
The mechanism of action of antibiotics are as follows:
|Targets of antibiotics||Mechanisms of action of antibiotics||Antibiotics|
|Cell Wall||Bactericidal, inhibit biosynthesis of peptidoglycan, inhibit or disrupt the peptidoglycan cross-linkage, disrupt precursor movement||Beta-lactam: Penicillin, Cephalosporin (ceftriaxone, cefotaxime), carbapenem (meropenem) Monobactam|
|Cytoplasmic membrane||Bactericidal, but toxic to humans as well, only used in a limited amount. Antibiotics increase cell permeability so that cellular contents are leaked out from the cell.||Polymyxins (for Gram-negatives)|
Gramicidin, Tyrocidine (for Gram positives)
|Protein synthesis||Both bactericidal and bacteriostatic, act on the 50s and the 30s subunits and halt protein synthesis.||Acting on 50s: |
Acting in the 30s:
Aminoglycosides: Streptomycin, Gentamycin, Neomycin, Kanamycin, Tobramycin, Amikacin
|Nucleic acid synthesis||Bactericidal antibiotics interfering with bacterial DNA and RNA synthesis||Acting on DNA gyrase:|
Quinolones: Nalidixic acid
Fluoroquinolones: Ciprofloxacin, Norfloxacin, Ofloxacin
Acting on RNA polymerase:
|Folate synthesis||Bacteriostatic, inhibit the synthesis of DHF and THF.||Inhibit PABA to DHF: Sulfonamide |
Inhibit DHF to THF: Trimethoprim
Bactericidal is an agent that kills bacteria whereas bacteriostatic is an agent that inhibits the growth and reproduction of bacteria but does not necessarily kill them.
Inhibition of cell wall synthesis
The bacterial cell wall comprises several layers of peptidoglycan, consisting of peptide chains and glycans (sugars). The cell wall glycans are made of N- acetyl muramic acid (NAM) and N-acetyl glucosamine (NAG). Transglycosidases aid the cross-linking of these sugars. Similarly, the peptide chain’s D- alanyl-D- alanine portion is cross-linked by glycine residues in the presence of penicillin-binding proteins (PBP). This cross-linking strengthens the cell wall. Different antibiotics inhibiting cell wall synthesis by various mechanisms are given below.
- Glycopeptides: The glycopeptides bind to the D-alanyl D- alanine portion of the peptide side chain of the precursor peptidoglycan subunit. The large drug molecule vancomycin prevents the binding of the D-alanyl subunit with the PBP inhibiting the peptidoglycan synthesis.
- Beta-lactam antibiotics: The primary targets of such antibiotics are PBPs. The Beta-lactam ring mimics the peptide chain’s D- alanine portion, usually bound by PBP. PBP then interacts with the beta-lactam ring and is not available for transpeptidation, then the synthesis of new peptidoglycan is blocked. This disruption of the peptidoglycan layer leads to bacterial lysis.
- Bacitracin: Antibiotics like bacitracin block the movement of precursors, which is required for peptidoglycan formation.
Inhibition of membrane function
The cytoplasmic membrane possesses selective permeability. Thus, its active transport system controls micro-and macro-molecules and ions in and out via integral transporter proteins. As the cytoplasmic membrane comprises fatty acids, the antibiotics target fatty acid synthesis and membrane phospholipids. Such antibiotics induce random pores by detergent-like activity, which leads to cellular molecules’ leakage, respiration inhibition, increased water uptake, and ultimately, cell death. Gram-positive bacteria have a thicker cell wall that protects the cell membrane. Hence Gram-positive bacteria are naturally resistant to such antibiotics.
Polymyxin B antibiotic has lipophilic and hydrophilic groups that disrupt fats leading to pore formation and cell death.
Inhibition of protein synthesis
mRNA is prepared using the information in the DNA. Furthermore, the ribosome makes proteins from genetic codes present in mRNA. Prokaryotic 70s ribosome has two subunits, the 30s and the 50s. Antibiotics target them and inhibit protein synthesis.
Inhibitors of the 30s
- Aminoglycosides: Aminoglycosides interact with rRNA of the 30s subunit near the A site and inhibit translocation. It results in misleading and premature termination of translation.
- Tetracycline: These antibiotics act on the conserved sequences of 16s rRNA to prevent tRNA binding to the A site.
Inhibitors of 50s subunit
- Chloramphenicol: It interacts with the conserved sequences of the peptide transferase cavity of the 23s rRNA, preventing the binding of tRNA to the A site of the ribosome. Chloramphenicol can enter the blood-brain barrier. Therefore, these antibiotics are used to treat central nervous system infections.
- Macrolides, lincosamides, streptogramins B: These antibiotics target the peptidyl transferase center of the 23s rRNA of the 50s ribosomal unit. It results in the premature detachment of the incomplete peptide chain.
- Oxazolidone: These antibiotics interfere with protein synthesis by binding to 23s r RNA of 50s subunit.
Inhibition of nucleic acid synthesis
DNA and RNA are essential for the growth and reproduction of bacteria. Some antibiotics, like rifamycin, target the synthesis of RNA and others target the replication of DNA. For targeting these nucleic acids, the antibiotics must easily pass the barrier (bacterial membranes) and attach to certain sites blocking their formation.
Inhibitors of transcription of RNA
- Rifamycin: Rifamycin is the subclass of anasymcins. This target the DNA-dependent RNA polymerase which blocks the initiation of transcription. Likewise, it also blocks the addition of nucleotides preventing the elongation of RNA. They do not interact with mammalian RNA but has a broad range of effect on gram-positive bacteria and some gram-negative bacteria.
Inhibitors of replication of DNA
- Quinolones and fluoroquinolones: These interfere with the coiling of DNA by inhibiting bacterial type II topoisomerases (DNA gyrase and topoisomerase IV). Quinolones bind to the active site of topoisomerase and fluoroquinolones form the DNA-enzyme complex to interrupt the binding of the two strands of the DNA. These specifically only target bacterial topoisomerase.
- Anthracyclines: These prevent the synthesis of both DNA and RNA in mammalian cells as well as bacterial cells. These either directly bind to the DNA strand or DNA topoisomerase II complex by forming a covalent bond.
Inhibition of folic acid synthesis
Folic acid is necessary for DNA and RNA synthesis, growth, and multiplication. Folic acid is supplied in humans through diet, whereas bacteria must synthesize folic acid. Para-aminobenzoic acid (PABA) is a substrate for folic acid synthesis.
Sulfonamides and trimethoprim inhibit different steps in folic acid synthesis. Sulfonamide shows a structural analogy with PABA, and it has a higher affinity for the enzyme, dihydropteroate synthase, than the natural substrate, PABA. Thus, sulfonamide inhibits the enzyme synthesizing dihydrofolate (DHF) from PABA.
Trimethoprim acts later in folic acid synthesis; it inhibits the enzyme dihydrofolate reductase to synthesize tetrahydrofolate (THF). The combination of sulfonamide and trimethoprim shows synergy and reduces the mutation rate for the resistance.
Challenges with the working of antibiotics
The mechanisms of action of antibiotics may face some obstacles, which are listed below.
- Antibiotic Resistance
Antibiotics discovery is one of the most outstanding achievements in medical science. Due to the high efficiency of antibiotics, various serious diseases are under control. But, with time, bacteria become smarter. Bacteria make resistance genes to protect themselves from antibiotics. Bacteria undergo mutation to be resistant to antibiotics to overcome the massive usage. Bacterial resistance to antibiotics may be due to the modification of the target molecule or the inactivation of antibiotics. Some bacteria show resistance by efflux mechanism, while others show altered permeability or bypass of the metabolic pathway.
The laboratories should perform antibiotic sensitivity tests, MBC, and MIC tests. It helps clinicians recommend the right type and dose of antibiotics to minimize antibiotic resistance.
- Side Effects
Some antibiotics show various side effects in the host after the administration. The side effects range from mild to severe, like fever and nausea, to significant allergic reactions, including anaphylaxis. A common side effect of most antibiotics is diarrhea, as antibiotics destroy the protective lining of intestinal flora. Due to potential adverse side effects, antibiotics must also be tested for their selective toxicity.
- Etebu E & Arikekpar I (2016). Antibiotics: Classification and Mechanisms of Action with Emphasis on Molecular Perspectives. International Journal of Applied Microbiology and Biotechnology Research 90-101.
- Kirmusaoglu et al. (2019). Introductory Chapter: The Action Mechanisms of Antibiotics and Antibiotic Resistance. DOI: 10.5772/intechopen.85211
- Kapoor et al. ( 2017). Action and Resistance Mechanisms of Antibiotics: A Guide for Clinicians. J Anasthesiol Clin Pharmacol. 33(3): 300-305. DOI: 10.4103/joacp.JOACP_349_15
- Antibiotics and Selective Toxicity. Biology LibreTextshttps://bio.libretexts.org/Bookshelves/Microbiology/Book%3A_Microbiology_(Boundless)/13%3A_Antimicrobial_Drugs/13.1%3A