Pharmaceutical Microbiology (Note 4)

MCB 525

500 Level

Streptomycin

Streptomycin is an antibiotic (antimycobacterial) drug, the first of a class of drugs called aminoglycosides to be discovered, and it was the first antibiotic remedy for tuberculosis. It is derived from the actinobacterium Streptomyces griseus. Streptomycin is a bactericidal antibiotic. Streptomycin cannot be given orally, but must be administered by regular intramuscular injections. Adverse effects of this medicine are ototoxicity, nephrotoxicity, fetal auditory toxicity, and neuromuscular paralysis.

Mechanism of action

Streptomycin is a protein synthesis inhibitor. It binds to the small S12 rRNA of the 30S subunit of the bacterial ribosome, interfering with the binding of formyl-methionyl-tRNA to the 30S subunit. This leads to codon misreading, eventual inhibition of protein synthesis and ultimately death of microbial cells through mechanisms that are still not understood. Speculation on this mechanism indicates that the binding of the molecule to the 30S subunit interferes with 50S subunit association with the mRNA strand. This results in an unstable ribosomal-mRNA complex, leading to a frameshift mutation and defective protein synthesis; leading to cell death. Humans have structurally different ribosomes from bacteria, thereby allowing the selectivity of this antibiotic for bacteria. At low concentrations, however, Streptomycin only inhibits growth of the bacteria by inducing prokaryotic ribosomes to misread mRNA. Streptomycin is an antibiotic that inhibits both Gram-positive and Gram-negative bacteria, and is therefore a useful broad-spectrum antibiotic.

History

Streptomycin was first isolated on October 19, 1943, by Albert Schatz, a graduate student, in the laboratory of Selman Abraham Waksman at Rutgers University. Dr. Waksman and his laboratory staff discovered several antibiotics, including actinomycin, clavacin, streptothricin, streptomycin, grisein, neomycin, fradicin, candicidin, and candidin. Of these, streptomycin and neomycin found extensive application in the treatment of numerous infectious diseases. Streptomycin was the first antibiotic that could be used to cure the disease tuberculosis (TB). Early production of the drug was dominated by Merck & Co. under George W. Merck.

The first randomized trial of streptomycin against pulmonary tuberculosis was carried out in 1946–1947 by the MRC Tuberculosis Research Unit under the chairmanship of Sir Geoffrey Marshall (1887–1982). The trial was both double-blind and placebo-controlled. It is widely accepted to have been the first randomised curative trial.

Results showed efficacy against TB, albeit with minor toxicity and acquired bacterial resistance to the drug. 

Uses

Treatment of diseases

• Infective endocarditis caused by enterococcus when the organism is not sensitive to Gentamicin
• Tuberculosis in combination with other anti-TB drugs. It is not the first-line treatment, except in medically under-served populations where the cost of more expensive treatments is prohibitive.
• Plague (Yersinia pestis) has historically been treated with it as the first-line treatment. It is approved for this purpose by the U.S. Food and Drug Administration.
• In veterinary medicine, streptomycin is the first-line antibiotic for use against gram negative bacteria in large animals (horses, cattle, sheep, etc.). It is commonly combined with procaine penicillin for intramuscular injection.

While streptomycin traditionally is given intramuscularly (indeed, in many countries it is only licensed to be used intramuscularly), the drug may also be administered intravenously.

Pesticide and fungicide

Streptomycin also is used as a pesticide, to combat the growth of bacteria, fungi, and algae. Streptomycin controls bacterial and fungal diseases of certain fruit, vegetables, seed, and ornamental crops, and it controls algae in ornamental ponds and aquaria. A major use is in the control of fireblight on apple and pear trees. As in medical applications, extensive use can be associated with the development of resistant strains.

Cell culture

Streptomycin, in combination with penicillin, is used in a standard antibiotic cocktail to prevent bacterial infection in cell culture.

Protein purification

When purifying protein from a biological extract, streptomycin sulfate is sometimes added as a means of removing nucleic acids. Since it binds to ribosomes and precipitates out of solution, it serves as a method for removing rRNA, mRNA, and even DNA if the extract is from a prokaryote.

Side Effects of Use

Fever and rashes result from persistent use. The Vestibular portion of cranial nerve VIII (the vestibulococlear nerve) can be affected, resulting in tinitus, vertigo and ataxia. It can also lead to nephrotoxicity.