The Groundbreaking Discovery of a Wonder Drug
Streptomycin was isolated in 1943 by Albert Schatz, Elizabeth Bugie, and Selman Waksman from the soil bacterium Streptomyces griseus [1.7.1]. Its discovery marked a pivotal moment in medicine, as it was the first effective chemotherapeutic agent against Mycobacterium tuberculosis, the bacterium that causes tuberculosis [1.7.2]. Before streptomycin, a tuberculosis diagnosis was often a death sentence. This new "wonder drug" offered hope and a tangible treatment, earning Selman Waksman the Nobel Prize in Physiology or Medicine in 1952 for his systematic search for antibiotics from microbes [1.7.1, 1.7.4]. Initially used as a monotherapy, it was soon discovered that bacteria quickly developed resistance, paving the way for the combination therapy protocols that are standard today [1.11.4].
How Does Streptomycin Work? The Primary Mechanism of Action
Streptomycin is a bactericidal aminoglycoside antibiotic, meaning it actively kills bacteria [1.2.2]. Its primary mechanism of action targets the intricate machinery of bacterial protein synthesis.
Binding to the Ribosomal Subunit
The core of streptomycin's action lies in its ability to bind to the bacterial ribosome, specifically to the smaller 30S subunit [1.3.1]. The ribosome is the cell's factory for producing proteins essential for its survival and replication. By targeting this structure, streptomycin effectively halts production.
The binding site is on the 16S ribosomal RNA (rRNA) component of the 30S subunit, near key decoding regions [1.2.2, 1.2.5]. This binding is irreversible and involves interactions with both the rRNA backbone and the ribosomal protein S12 [1.3.2].
Inducing Errors in Protein Synthesis
Once bound, streptomycin causes significant disruptions to the ribosome's function in two main ways:
- Inhibition of Initiation: It interferes with the binding of the initiator tRNA (formyl-methionyl-tRNA) to the 30S subunit. This prevents the formation of the initiation complex, a critical first step for protein synthesis to begin [1.4.3].
- mRNA Misreading: For ribosomes that have already initiated translation, streptomycin induces large distortions in the ribosome's structure [1.2.1]. This distortion impairs the ribosome's proofreading capability, causing it to misread the genetic code on the messenger RNA (mRNA) strand. Consequently, the ribosome incorporates incorrect amino acids into the growing polypeptide chain [1.2.1, 1.2.5].
The production of these faulty, non-functional proteins disrupts numerous vital cellular processes, leading to membrane damage and ultimately, bacterial cell death [1.2.1, 1.3.1].
Spectrum of Activity and Clinical Applications
Streptomycin is a broad-spectrum antibiotic, though its modern use is more targeted due to resistance and the availability of newer agents [1.11.4]. It is primarily active against aerobic gram-negative bacteria and Mycobacterium tuberculosis [1.8.2, 1.8.3]. Because its transport into the bacterial cell is an oxygen-dependent process, it is not effective against anaerobic bacteria [1.2.2].
Its main clinical uses include:
- Tuberculosis (TB): It is a first-line agent, almost always used as part of a multi-drug regimen to treat active TB and prevent the emergence of resistance [1.4.1, 1.11.4].
- Tularemia: An infection caused by Francisella tularensis, for which streptomycin has historically been a primary treatment [1.4.3, 1.9.4].
- Plague: Caused by Yersinia pestis, streptomycin is an FDA-approved treatment [1.4.3].
- Bacterial Endocarditis: Used in combination with other drugs for certain types of heart valve infections, such as those caused by Enterococcus species [1.4.4].
Comparison of Aminoglycosides: Streptomycin vs. Gentamicin
Streptomycin and gentamicin are both potent aminoglycoside antibiotics that inhibit protein synthesis, but they have key differences.
| Feature | Streptomycin | Gentamicin |
|---|---|---|
| Primary Use | Primarily Tuberculosis (in combination therapy), plague, tularemia [1.4.1, 1.4.3] | Broad-spectrum treatment for severe gram-negative infections, including Pseudomonas aeruginosa [1.9.2] |
| Toxicity Profile | High risk of ototoxicity (especially vestibular/balance issues); less nephrotoxic than other aminoglycosides [1.5.1, 1.11.4]. | High risk of both nephrotoxicity (kidney damage) and ototoxicity (hearing loss) [1.9.3, 1.5.5]. |
| Resistance | Resistance developed rapidly when used as monotherapy. Not much cross-resistance with other aminoglycosides [1.6.1, 1.11.4]. | Resistance is a growing concern; often used for more severe, hospital-acquired infections [1.9.2]. |
| Administration | Intramuscular (IM) injection is typical [1.4.3]. | Intravenous (IV) or Intramuscular (IM) injection [1.11.2]. |
Bacterial Resistance to Streptomycin
Bacterial resistance to streptomycin can emerge rapidly and occurs through several primary mechanisms [1.6.1]:
- Target Site Modification: This is the most common mechanism. Mutations in the rpsL gene, which codes for the ribosomal protein S12, or in the 16S rRNA gene itself, can alter the binding site [1.2.5, 1.6.2]. These changes prevent streptomycin from binding effectively to the ribosome, rendering the drug useless.
- Enzymatic Inactivation: Some bacteria possess genes, often on plasmids, that produce enzymes like phosphotransferases. These enzymes chemically modify the streptomycin molecule, inactivating it before it can reach its ribosomal target [1.6.1, 1.6.4].
- Efflux Pumps: Certain bacteria have evolved to produce membrane proteins that act as pumps, actively transporting streptomycin out of the cell before it can accumulate to a bactericidal concentration [1.6.2].
Adverse Effects and Monitoring
Streptomycin's use is limited by its potential for significant toxicity. Regular monitoring is essential during treatment [1.4.2].
- Ototoxicity: This is a major side effect, involving damage to the eighth cranial nerve. It can cause permanent hearing loss (cochlear toxicity) and/or dizziness, vertigo, and balance problems (vestibular toxicity) [1.5.2, 1.5.4]. The risk is related to the cumulative dose [1.6.1].
- Nephrotoxicity: Streptomycin can cause kidney damage, though it is generally considered less nephrotoxic than other aminoglycosides like gentamicin [1.5.2, 1.11.4]. This damage is often reversible upon discontinuation of the drug [1.5.1].
- Neuromuscular Blockade: A rarer side effect where the drug interferes with nerve signals to muscles [1.5.5].
Conclusion
Streptomycin works by binding to the bacterial 30S ribosomal subunit, a critical component of protein synthesis. This action leads to the creation of faulty proteins and ultimately kills the bacterium. Although its use has been curtailed by bacterial resistance and significant side effects like ototoxicity, it remains a vital medication in the combination treatment of tuberculosis and other specific, serious infections [1.11.1, 1.11.3]. Understanding its mechanism is crucial for its effective use and for the development of future antibiotics.
For more information from an authoritative source, consider visiting the CDC's page on Tuberculosis Treatment..
