streptomycin

streptomycin
IUPAC name	2-[(1S,2R,3R,4S,5R,6S)-3-(diaminomethylideneamino)-4-[(2R,3R,4R,5S)-3-[(2S,3S,4S,5R,6S)-4,5-dihydroxy-6-(hydroxymethyl)-3-(methylamino)oxan-2-yl]oxy-4-formyl-4-hydroxy-5-methyloxolan-2-yl]oxy-2,5,6-trihydroxycyclohexyl]guanidine
Width	200
Verifiedrevid	477102174
Tradename	Strepto
Drugs.com	international, streptomycin
Legal AU	S4
Legal UK	POM
Legal US	Rx-only
Routes of administration	Intramuscular, intravenous
CAS number	57-92-1
ATC prefix	A07
ATC suffix	AA04
PubChem	19649
DrugBank	DB01082
ChemSpiderID	18510
UNII	Y45QSO73OB
KEGG	D07845
ChEBI	17076
ChEMBL	1777
Chemical formula	C21H39N7O12
Molecular weight	581.574 g/mol
Melting point	12
Melting high	25
Melting notes	(as sulfate)

streptomycin. It is an aminoglycoside antibiotic derived from the actinobacterium Streptomyces griseus. The discovery of this compound by Selman Waksman and his team at Rutgers University represented a monumental breakthrough, providing the first effective treatment for tuberculosis and earning Waksman the Nobel Prize in Physiology or Medicine. It functions by binding to the bacterial ribosome, disrupting protein synthesis and leading to microbial cell death.

History

The isolation of this agent was announced in 1944 by Selman Waksman, Albert Schatz, and Elizabeth Bugie following extensive research into soil microorganisms at Rutgers University. This work was heavily supported by grants from the Merck & Co. pharmaceutical firm. Its immediate efficacy against Mycobacterium tuberculosis was demonstrated in clinical trials conducted at the Mayo Clinic and other institutions, revolutionizing the treatment of tuberculosis. The awarding of the Nobel Prize in Physiology or Medicine to Waksman in 1952 solidified its historical importance, though it also led to a protracted controversy over credit with Schatz. Its success spurred the World Health Organization to initiate global anti-tuberculosis campaigns and inspired further exploration of actinomycetes for drug discovery.

Medical uses

Its primary historical and continued use is as a first-line agent for the treatment of tuberculosis, typically administered in combination with isoniazid and rifampin to prevent resistance. It is also employed as an alternative therapy for plague caused by Yersinia pestis and for the treatment of brucellosis, often combined with doxycycline. In veterinary medicine, it is used to combat infections in livestock. Due to its potential for toxicity and the development of newer agents, its systemic use has declined, but it remains on the World Health Organization List of Essential Medicines.

Mechanism of action

As an aminoglycoside, it exerts its bactericidal effect by irreversibly binding to the 16S ribosomal RNA component of the 30S subunit of the bacterial ribosome. This binding occurs at a specific site within the A site, which interferes with the initiation complex during protein synthesis and causes misreading of the genetic code. The resultant production of faulty, non-functional proteins disrupts critical cellular processes and compromises the integrity of the cell membrane, ultimately leading to cell death. This action is concentration-dependent and is most effective against aerobic, gram-negative bacteria.

Adverse effects

Significant adverse effects limit its clinical utility, with ototoxicity being a major concern, potentially causing irreversible damage to the vestibular system and resulting in vertigo and loss of balance. Nephrotoxicity is another serious risk, as it can impair renal function by damaging the proximal tubule. Neuromuscular blockade is a rare but dangerous effect that can lead to respiratory paralysis. Allergic reactions, including skin rash and drug fever, can also occur. Patients undergoing treatment require careful monitoring of auditory function and renal plasma flow.

Production and synthesis

It is produced industrially via the fermentation of the soil bacterium Streptomyces griseus in large-scale bioreactors. The process involves cultivating the organism in a complex nutrient medium, often containing sources like soybean meal and glucose, under controlled conditions of aeration and temperature. Following fermentation, the compound is extracted from the broth using filtration and purified through techniques such as ion-exchange chromatography and crystallization, typically as the sulfate salt. While the complete chemical synthesis has been achieved in laboratories, it is not economically viable for commercial production compared to fermentation.

Resistance

Bacterial resistance can arise through several mechanisms, the most common being enzymatic modification by aminoglycoside-modifying enzymes such as adenylyltransferase or phosphotransferase, which inactivate the drug. A second major mechanism involves mutations in the genes encoding the 16S ribosomal RNA or ribosomal proteins, particularly in the rpsL gene, which alter the drug's target site and reduce its binding affinity. Reduced membrane permeability, often seen in Pseudomonas aeruginosa, and active efflux pumps also contribute to resistance. The use of combination therapy in treating tuberculosis is a direct strategy to delay the emergence of these resistant mutants.

Category:Aminoglycoside antibiotics Category:World Health Organization essential medicines Category:Anti-tuberculosis drugs