What is the mechanism of action of streptomycin? Understanding How This Antibiotic Works

October 6, 2025 •

5 min read

First isolated in 1943 from the bacterium Streptomyces griseus, streptomycin was the first effective antibiotic discovered for treating tuberculosis. As an aminoglycoside, its core function is to disrupt bacterial protein synthesis, but the precise details of what is the mechanism of action of streptomycin involve a lethal cascade of events triggered by its binding to the bacterial ribosome.

Quick Summary

Streptomycin is an aminoglycoside antibiotic that exerts its bactericidal effects by inhibiting protein synthesis. It binds irreversibly to the 30S ribosomal subunit of bacteria, causing the misreading of mRNA and disrupting the formation of the protein synthesis initiation complex.

Key Points

Binding Site: Streptomycin irreversibly binds to the 30S ribosomal subunit of bacteria, specifically interacting with the 16S rRNA and the S12 ribosomal protein.
Inhibition of Protein Synthesis: The antibiotic disrupts the translation process by interfering with the formation of the initiation complex and promoting the misreading of the genetic code.
mRNA Misreading: Streptomycin stabilizes incorrect tRNA-mRNA pairings, causing the ribosome to insert incorrect amino acids and produce faulty, non-functional proteins.
Bactericidal Effect: The lethal combination of producing misfolded proteins and halting synthesis ultimately leads to the death of the bacterial cell.
Energy-Dependent Uptake: Streptomycin requires an oxygen-dependent electron transport system to enter the bacterial cell, making it ineffective against anaerobic bacteria.
Resistance Mechanisms: Bacteria can develop resistance through mutations in the ribosome, enzymatic modification of the drug, or the use of efflux pumps to expel the antibiotic.
Toxicity: A key side effect of streptomycin and other aminoglycosides is ototoxicity, which can cause both vestibular (balance) and cochlear (hearing) dysfunction.

How Streptomycin Enters the Bacterial Cell

Streptomycin, like all aminoglycoside antibiotics, is a hydrophilic molecule, meaning it does not easily pass through the lipid-rich bacterial cell membrane. Therefore, its entry into the bacterial cytoplasm is an energy-dependent process. This uptake requires an electron transport system, which is part of the bacterium's respiratory chain.

Initial Binding: Streptomycin is first attracted to the negatively charged outer surface of the bacterial cell through electrostatic interactions.
Energy-Dependent Transport: The antibiotic is then actively transported across the cell membrane into the cytoplasm via the electron transport chain. This dependence on an active respiratory system means that aminoglycosides like streptomycin are primarily effective against aerobic bacteria, which rely on this type of metabolism.
Membrane Damage (Hypothesized): Some research suggests that once inside the cell, streptomycin can also cause general damage to the cell membrane, leading to the leakage of potassium ions and other essential components. This further destabilizes the cell and facilitates the entry of more antibiotic, contributing to the bactericidal effect.

Binding to the 30S Ribosomal Subunit

The primary target of streptomycin within the bacterial cell is the ribosome, the complex molecular machine responsible for translating mRNA into proteins. Specifically, it targets the smaller 30S ribosomal subunit, a structure unique to prokaryotes, ensuring it does not interfere with the human ribosome (which has different subunits). The binding site is located near the decoding center on the 16S ribosomal RNA (rRNA) and the ribosomal protein S12.

Crystallographic studies have revealed that streptomycin induces significant conformational changes in the 30S subunit. It shifts the decoding site region, specifically displacing critical bases within the 16S rRNA (like A1492 and A1493). This distortion directly impacts the ribosome's ability to accurately read the genetic code.

Disrupting Protein Synthesis: Misfolding and Halt

By binding to the 30S ribosomal subunit, streptomycin causes two major disruptions to the process of protein synthesis:

mRNA Misreading: The conformational changes induced by streptomycin make the ribosome less able to discriminate between correct ("cognate") and incorrect ("near-cognate") transfer RNAs (tRNAs). This leads to a high rate of translational errors, causing the insertion of wrong amino acids into the growing polypeptide chain. The resulting proteins are faulty and non-functional, a state often referred to as an "error catastrophe".
Initiation Inhibition: Streptomycin also interferes with the formation of the initiation complex, the crucial step where the ribosome assembles on the mRNA to begin translation. By blocking the binding of the formyl-methionyl-tRNA to the 30S subunit, it prevents protein synthesis from starting correctly. At higher concentrations, this can cause premature termination and disrupt the stability of the ribosome-mRNA complex.

Consequences of Ribosomal Disruption

The dual impact of streptomycin—causing both misreading of existing proteins and preventing new ones from being made—is catastrophic for the bacterial cell. The accumulation of misfolded and non-functional proteins interferes with all cellular processes, while the halt in new protein production prevents cell growth and replication. Unlike bacteriostatic antibiotics that simply prevent growth, this mechanism is bactericidal, leading directly to the death of the bacterial cell.

Mechanisms of Resistance to Streptomycin

Over time, bacteria can develop resistance to streptomycin through several mechanisms. This was observed early in its clinical use when it was administered as a monotherapy for tuberculosis. The primary mechanisms include:

Enzymatic Inactivation: Some bacteria produce enzymes that can chemically modify and inactivate the streptomycin molecule. This is often facilitated by plasmid-borne genes that can be transferred between bacteria.
Target Site Modification: Mutations can occur in the genes encoding either the 16S rRNA or the S12 ribosomal protein. These mutations alter the structure of the binding site on the 30S subunit, preventing streptomycin from binding effectively or inducing the necessary conformational changes. Many resistant strains of Mycobacterium tuberculosis, for example, have mutations in the rpsL gene (encoding S12) or the rrs gene (encoding 16S rRNA).
Efflux Pumps: Certain bacteria can develop resistance by activating efflux pumps, which are membrane proteins that actively pump the antibiotic out of the cell, reducing its intracellular concentration and effectiveness.

Streptomycin Compared to Other Aminoglycosides

Streptomycin is one of several aminoglycoside antibiotics, which all share a similar mechanism of action but differ in their spectrum of activity, potency, and toxicity. The following table provides a brief comparison:


Feature	Streptomycin	Kanamycin	Amikacin	Capreomycin	Gentamicin/Tobramycin
Usage	Historically used for TB; now often a second-line drug in MDR-TB regimens.	Used for serious gram-negative infections; second-line for MDR-TB.	Superior activity against MDR-TB; effective against many resistant gram-negative organisms.	Peptide antibiotic, active against MDR-TB; less effective under anaerobic conditions.	Broad-spectrum activity, including Pseudomonas aeruginosa; less active on a weight basis than Amikacin.
Bactericidal	Yes	Yes	Yes	Yes, though may be less effective under anaerobic conditions	Yes
Toxicity	High ototoxicity (vestibular > cochlear); less nephrotoxic than others.	High ototoxicity and nephrotoxicity.	High ototoxicity and nephrotoxicity.	High ototoxicity and nephrotoxicity.	Significant ototoxicity and nephrotoxicity.
Resistance	Resistance emerges rapidly with monotherapy; mutations in rpsL and rrs.	Cross-resistance with streptomycin is uncommon; used in MDR-TB.	Often effective against gentamicin-resistant strains.	Differs from aminoglycosides in transport; often cross-resistance is not common with streptomycin.	Widely used, but resistance is a concern.

Conclusion

The mechanism of action of streptomycin is rooted in its irreversible binding to the bacterial 30S ribosomal subunit. This binding induces profound conformational changes that lead to two critical defects in protein synthesis: the misreading of mRNA and the inhibition of the translation initiation complex. The resulting accumulation of non-functional proteins and the cessation of new protein production ultimately lead to the death of the bacterial cell, classifying streptomycin as a bactericidal antibiotic. However, its effectiveness is limited by its inability to enter anaerobic bacteria and the development of resistance through mechanisms like target modification and enzymatic inactivation. Despite newer and less toxic alternatives, understanding the precise mechanism of streptomycin is vital for managing drug-resistant infections and provides valuable insight into the bacterial physiology it targets.

For further reading on the structural basis of streptomycin action, see the original research published by the Brookhaven National Laboratory at the following link: https://www.bnl.gov/newsroom/news.php?a=24251.

Frequently Asked Questions

Streptomycin's primary function is to inhibit bacterial protein synthesis, a critical process for cell growth and survival, by disrupting the function of the bacterial ribosome.

Streptomycin specifically targets the 30S subunit of the bacterial ribosome, binding to the 16S rRNA component and the S12 protein.

By binding to the 30S ribosomal subunit, streptomycin distorts the decoding site, which lowers the ribosome's ability to discriminate between correct and incorrect tRNAs, leading to a high rate of translational errors.

No, streptomycin does not typically affect human cells because it specifically targets the smaller 30S ribosomal subunit found only in prokaryotic bacteria, not the larger ribosomes of eukaryotes.

Streptomycin enters the bacterial cell through an energy-dependent process that relies on the bacterium's electron transport system, making it primarily effective against aerobic bacteria.

Streptomycin is bactericidal, meaning it kills bacteria rather than just inhibiting their growth. The production of faulty proteins and the halting of synthesis ultimately lead to cell death.

Bacteria develop resistance through several mechanisms, including mutations in ribosomal proteins or rRNA that alter the binding site, enzymatic inactivation of the antibiotic, and the activation of efflux pumps that remove the drug from the cell.

Streptomycin is often used in combination with other antibiotics to increase its efficacy, broaden the spectrum of coverage, and reduce the likelihood of resistance developing, which can occur rapidly when it is used alone.