Streptomycin

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| _other_data=5-(2,4-diguanidino-
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| _datapage = Streptomycin (data page) | _vaccine_target={{#ifeq: | vaccine | | _type_not_vaccine }} | _legal_all=S4POMRx-only | _ATC_prefix_supplemental=A07Template:ATC Template:ATC Template:ATC | _has_EMA_link = | CAS_number=57-92-1 | PubChem=19649 | ChemSpiderID=18508 | ChEBI=17076 | ChEMBL=1201194 | DrugBank=DB01082 | KEGG=D08531 | _hasInChI_or_Key={{#if:1S/C21H39N7O12/c1-5-21(36,4-30)16(40-17-9(26-2)13(34)10(31)6(3-29)38-17)18(37-5)39-15-8(28-20(24)25)11(32)7(27-19(22)23)12(33)14(15)35/h4-18,26,29,31-36H,3H2,1-2H3,(H4,22,23,27)(H4,24,25,28)/t5-,6-,7+,8-,9-,10-,11+,12-,13-,14+,15+,16-,17-,18-,21+/m0/s1UCSJYZPVAKXKNQ-HZYVHMACSA-N |yes}} | UNII=Y45QSO73OB | _hasJmol02 = |_hasMultipleCASnumbers = |_hasMultiplePubChemCIDs = |_hasMultipleChEBIs =

| _countSecondIDs={{#invoke:ParameterCount |main |CAS_number2 |ATC_prefix2 |PubChem2 |PubChemStructure2 |IUPHAR_ligand2 |DrugBank2 |ChemSpiderID2 |UNII2 |KEGG2 |ChEBI2 |ChEMBL2 |PDB_ligand2 |NIAID_ChemDB2 |SMILES2 |smiles2 |StdInChI2 |StdInChIKey2 |DTXCID2}} | _countIndexlabels={{#invoke:ParameterCount |main |index_label |index2_label}} | _trackListSortletter= |QID = |QID2 = |Verifiedfields=changed |Watchedfields= |verifiedrevid=470471096}} Template:Wikt Streptomycin is an antibiotic medication used to treat a number of bacterial infections,<ref name=AHFS2016/> including tuberculosis, Mycobacterium avium complex, endocarditis, brucellosis, Burkholderia infection, plague, tularemia, and rat bite fever.<ref name=AHFS2016/> For active tuberculosis it is often given together with isoniazid, rifampicin, and pyrazinamide.<ref name=WHO2008>Template:Cite book</ref> It is administered by injection into a vein or muscle.<ref name=AHFS2016>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Common side effects include vertigo, vomiting, numbness of the face, fever, and rash.<ref name=AHFS2016/> Use during pregnancy may result in permanent deafness in the developing baby.<ref name=AHFS2016/> Use appears to be safe while breastfeeding.<ref name=WHO2008/> It is not recommended in people with myasthenia gravis or other neuromuscular disorders.<ref name=WHO2008/> Streptomycin is an aminoglycoside.<ref name=AHFS2016/> It works by blocking the ability of 30S ribosomal subunits to make proteins, which results in bacterial death.<ref name=AHFS2016/>

Albert Schatz first isolated streptomycin in 1943 from Streptomyces griseus.<ref>Template:Cite book</ref><ref>Template:Cite book</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO21st">Template:Cite book</ref> The World Health Organization classifies it as critically important for human medicine.<ref>Template:Cite book</ref>

Uses

Medication

• Infective endocarditis: An infection of the endocardium caused by enterococcus; used when the organism is not sensitive to gentamicinTemplate:Medcn
• Tuberculosis: Used in combination with other antibiotics. For active tuberculosis it is often given together with isoniazid, rifampicin, and pyrazinamide.<ref name=WHO2008/> It is not the first-line treatment, except in medically under-served populations where the cost of more expensive treatments is prohibitive. It may be useful in cases where resistance to other drugs is identified.Template:Medcn
• Plague (Yersinia pestis): Has historically been used as the first-line treatment. However streptomycin is approved for this purpose only by the US Food and Drug Administration.Template:Medcn
• 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.Template:Medcn
• Tularemia infections have been treated mostly with streptomycin.<ref name=CDC2016Doc>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

Streptomycin is traditionally given intramuscularly, and in many nations is only licensed to be administered intramuscularly, though in some regions the drug may also be administered intravenously.<ref name="Zhu2001">Template:Cite journal</ref>

Pesticide

Streptomycin also is used as a pesticide, to combat the growth of bacteria beyond human applications. Streptomycin controls bacterial diseases of certain fruit, vegetables, seed, and ornamental crops. 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. Streptomycin could potentially be used to control cyanobacterial blooms in ornamental ponds and aquaria.<ref name="pmid20725941">Template:Cite journal</ref> While some antibacterial antibiotics are inhibitory to certain eukaryotes, this seems not to be the case for streptomycin, especially in the case of anti-fungal activity.<ref name="pmid16560957">Template:Cite journal</ref>

Cell culture

Streptomycin, in combination with penicillin, is used in a standard antibiotic cocktail to prevent bacterial infection in cell culture.<ref name="Phelan2015">Template:Cite journal</ref>

Protein purification

When purifying protein from a biological extract, streptomycin sulfate is sometimes added as a means of removing nucleic acids and ribonuclear proteins. 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.<ref name="Scopes 1994 p. ">Template:Cite book</ref>

Side effects

The most concerning side effects, as with other aminoglycosides, are kidney toxicity and ear toxicity.<ref name="pmid20627927">Template:Cite journal</ref> Transient or permanent deafness may result. The vestibular portion of cranial nerve VIII (the vestibulocochlear nerve) can be affected, resulting in tinnitus, vertigo, ataxia, kidney toxicity, and can potentially interfere with diagnosis of kidney malfunction.<ref>Template:Cite journal</ref>

Common side effects include vertigo, vomiting, numbness of the face, fever, and rash. Fever and rashes may result from persistent use.Template:Citation needed

Use is not recommended during pregnancy.<ref name=AHFS2016/> Congenital deafness has been reported in children whose mothers received streptomycin during pregnancy.<ref name="AHFS2016" /> Use appears to be okay while breastfeeding.<ref name=WHO2008/>

It is not recommended in people with myasthenia gravis.<ref name=WHO2008/>

Mechanism of action

Streptomycin functions as a protein synthesis inhibitor. It binds to the small 16S rRNA of the 30S ribosomal subunit irreversibly, interfering with the binding of formyl-methionyl-tRNA to the 30S subunit.<ref>Template:Cite journal </ref> This causes codon misreading, inhibition of protein synthesis, and ultimately death of the cell through mechanisms that are not well understood. Speculation indicates that the binding of the molecule to the 30S subunit interferes with 30S subunit association with the mRNA strand. This results in an unstable ribosomal-mRNA complex, leading to premature stopping of protein synthesis, leading to cell death.<ref>Template:Cite book</ref> As human and bacteria both have ribosomes, streptomycin has significant side effects in humans. At low concentrations, however, streptomycin inhibits only bacterial growth.<ref> Template:Cite book </ref>

Streptomycin is an antibiotic that inhibits both Gram-positive and Gram-negative bacteria,<ref name="SchantzNg2004">Template:Cite book</ref> and is therefore a useful broad-spectrum antibiotic.

History

Streptomycin was first isolated on October 19, 1943, by Albert Schatz, a PhD student in the laboratory of Selman Abraham Waksman at Rutgers University in a research project funded by Merck and Co.<ref> Template:Cite journal </ref><ref>Template:Cite journal</ref> 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 cure for tuberculosis (TB). In 1952 Waksman was the recipient of the Nobel Prize in Physiology or Medicine in recognition "for his discovery of streptomycin, the first antibiotic active against tuberculosis".<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Waksman was later accused of playing down the role of Schatz who did the work under his supervision, claiming that Elizabeth Bugie had a more important role in its development.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="google">Template:Cite book</ref><ref name="pmid1882032">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite book</ref> Schatz sued both Dr. Waksman and the Rutgers Research and Endowment Foundation, wanting to be given credit as co-discover and to receive the royalties for the streptomycin.<ref name="scientistafoundation.com">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> By the end of the settlement, Waksman would receive a 10% royalty, while Schatz got 3% and compensation for his missed royalties.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The rest of the lab shared the remaining 7% of the royalties, in which Bugie received 0.2%.Template:Cn

Bugie was pursuing a master's degree in Waksman's lab at Rutgers University at this time. Prior to this, she received her bachelor's degree in microbiology at New Jersey College for Women.<ref name="scientistafoundation.com"/> Although Bugie was considered to be the second author on the Proceedings of the Society for Experimental Biology paper, she was not listed on the patent submission.<ref name="scientistafoundation.com"/> Bugie's contributions to Waksman's lab were great. In addition to her work on streptomycin, she also helped develop other antimicrobial substances,<ref>Template:Cite book</ref> had two peer-reviewed publications,<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> and researched the use of antimicrobials against plant pathogens,<ref>Template:Cite journal</ref> among several other important contributions to the scientific field, particularly in regard to microbiology.

File:Streptomycin assay.jpg

A scientist at Rutger's University making a streptomycin assay.

The Rutgers team reported streptomycin in the medical literature in January 1944.<ref name="DOI-ending-in-00379727-55-14461">Template:Cite journal</ref> Within months they began working with William Feldman and H. Corwin Hinshaw of the Mayo Clinic with hopes of starting a human clinical trial of streptomycin in tuberculosis.<ref name="Ryan_1993">Template:Cite book</ref>Template:Rp The difficulty at first was even producing enough streptomycin to do a trial, because the research laboratory methods of creating small batches had not yet been translated to commercial large-batch production. They managed to do an animal study in a few guinea pigs with just 10 grams of the scarce drug, demonstrating survival.<ref name="Ryan_1993"/>Template:Rp This was just enough evidence to get Merck & Co. to divert some resources from the young penicillin production program to start work toward streptomycin production.<ref name="Ryan_1993"/>Template:Rp

At the end of World War II, the United States Army experimented with streptomycin to treat life-threatening infections at a military hospital in Battle Creek, Michigan. The first person who was treated with streptomycin did not survive; the second person survived but became blind as a side effect of the treatment. In March 1946, the third person—Robert J. Dole, later Majority Leader of the United States Senate and presidential nominee—experienced a rapid and robust recovery.<ref>Template:Cite book</ref>

The first randomized trial of streptomycin against pulmonary tuberculosis was carried out in 1946 through 1948 by the MRC Tuberculosis Research Unit under the chairmanship of Geoffrey Marshall (1887–1982). The trial was neither double-blind nor placebo-controlled.<ref name="pmid10463905"/> It is widely accepted to have been the first randomized curative trial.<ref>Template:Cite journal</ref>

Results showed efficacy against TB, albeit with minor toxicity and acquired bacterial resistance to the drug.<ref name="pmid10463905">Template:Cite journal</ref>

New Jersey

Because streptomycin was isolated from a microbe discovered on New Jersey soil, and because of its activity against tuberculosis and Gram negative organisms, and in recognition of both the microbe and the antibiotic in the history of New Jersey, S. griseus was nominated as the Official New Jersey state microbe. The draft legislation was submitted by Senator Sam Thompson (R-12) in May 2017 as bill S3190 and Assemblywoman Annette Quijano (D-20) in June 2017 as bill A31900. The bill was passed on 2018-01-08 The bill designates Streptomyces griseus as New Jersey State Microbe (New Jersey Senate Bill 3190 (2017). Governor Phil Murphy signed the bill making it official in 2019.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Further reading

• Greenwood, David. Antimicrobial Drugs: Chronicle of a twentieth century medical triumph (Oxford University Press, 2008) summary

• Template:Cite journal
• Template:Cite news. The history behind the discovery of streptomycin.
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