Tetracyclines: Mode of Action and Mechanism of Resistance
Tetracyclines are a group of broad-spectrum antibiotics effective against a wide range of Gram-positive, Gram-negative bacteria, and several intracellular bacterial pathogens such as chlamydia, rickettsia, mycoplasma, etc. Tetracyclines are usually considered as bacteriostatic antibiotics.
The first tetracycline antibiotic, chlortetracycline and oxytetracycline were discovered in the late 1940s, and were derived naturally from Streptomyces aureofaciens and S. rimosus, respectively. Currently there are various semi-synthetic tetracyclines available.
Structurally, tetracycline molecules comprise a linear fused tetracyclic nucleus (rings designated A, B, C, and D) to which a variety of functional groups are attached.
Classification of Tetracyclines
Conventionally, tetracyclines have three generations;
- First-generation include tetracyclines which are obtained from biosynthesis such as, chlortetracycline, oxytetracycline.
- Second generation tetracyclines comprise of doxycycline, minocycline, etc. obtained from semi-synthesis of tetracycline.
- Third generation includes tigecycline, which obtained from total synthesis.
Mode of Action of Tetracyclines
Tetracyclines inhibit bacterial protein synthesis through reversible binding to bacterial 30S ribosomal subunits, which prevent binding of new incoming amino acids (aminoacyl-tRNA) and thus interfere with peptide growth.
Resistance Mechanism against Tetracyclines
Molecular mechanisms of tetracycline resistance include 1. efflux 2. ribosomal protection 3. reduced permeability 4. ribosome mutation and 5. enzymatic inactivation
A major way to limit access of tetracycline to ribosomes is to reduce intracellular concentrations of tetracycline by pumping the antibiotic out of the cell at a rate equal to or greater than its uptake. There are various classes of efflux pumps present in both Gram-negative and Gram-positive bacteria. Of them, TetA, is the most frequently occurring tetracycline-resistance determinant in Gram-negative bacteria. Efflux proteins exchange a proton (H+) for the tetracycline molecule against a concentration gradient and pump out the tetracycline from the cell. Most tetracycline efflux pumps confer resistance to tetracycline, but are less effective against second-generation doxycycline and minocycline, and confer little or no resistance to third-generation glycylcyclines, such as tigecycline.
Acquired tetracycline resistance is mediated by the production of elongation-factor G (EF-G)-like ribosomal protection proteins that interact with the ribosome in such a way that protein synthesis is unaffected by the presence of the antibiotic. The most common determinants of ribosomal protection have been those encoded by the tet(M) and tet(O) genes.
Reduced Drug Permeability
This is achieved through morphological changes and the modification or reduced expression of porins and likely contributes to clinical tetracycline resistance.
This mechanism is less common in conferring resistance to tetracyclines, however, some resistance-conferring mutations and deletions around the tetracycline-binding site, point mutations in the 16S ribosome also confer tetracycline resistance.
A group of enzymes called tetracycline destructase selectively oxidize tetracyclines leading to covalent destruction of the antibiotic scaffold thus destroying antimicrobial activity permanently. Newer generation of tetracyclines such as minocycline and tigecycline, which resist efflux pumps and ribosomal protection are also affected by these mechanisms of resistance.
References and Further Readings
- Askari Rizvi, S. F. (2018). Tetracycline: Classification, Structure Activity Relationship, and Mechanism of Action as a Theranostic Agent for Infectious Lesions-A Mini-Review. Biomedical Journal of Scientific & Technical Research, 7(2).
- Chopra, I., & Roberts, M. (2001). Tetracycline Antibiotics: Mode of Action, Applications, Molecular Biology, and Epidemiology of Bacterial Resistance. Microbiology and Molecular Biology Reviews, 65(2), 232–260.
- Markley, J. L., & Wencewicz, T. A. (2018). Tetracycline-Inactivating Enzymes. Frontiers in Microbiology, 9.