Aminoglycoside

Introduction
These are a group of natural and semisynthetic antibiotics having polybasic amino groups linked glycosidically to two or more aminosugar (streptidine, 2-deoxy streptamine, garosamine ) residues. Unlike penicillin, which was a chance discovery, aminoglycosides are products of deliberate search for drug effective against gram negative bacteria. Streptomycin was the first member discovered in 1944 by Waksman and his colleagues. It assumed gread importance because it was active against tuberclebacilli. Others have been produced later, now aminoglycosides are a sizable family. All aminoglycosides are produced by soil actinomycetes and have many common properties An aminoglycoside is a molecule or a portion of a molecule composed of amino-modified sugars[1] Several aminoglycosides function as antibiotics that are effective against certain types of bacteria. They include amikacin, arbekacin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, rhodostreptomycin,[2] streptomycin, tobramycin, and apramycin[3]. Systemic Aminoglycosides: Streptomycin Gentamicin Kanamycin Tobramycin Topical Aminoglycosides: Neomycin Framycetin Amikacin Sisomicin Netilmicin

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Mechanisms of action:
Aminoglycosides have several potential antibiotic mechanisms, some as protein synthesis inhibitors, although their exact mechanism of action is not fully known:

They interfere with the proofreading process, causing increased rate of error in synthesis with premature termination.[9]

Also, there is evidence of inhibition of ribosomal translocation where the peptidyl-tRNA moves from the A-site to the P-site.[9] They can also disrupt the integrity of bacterial cell membrane. [10]

They bind to the bacterial 30S ribosomal subunit[11][12] (some work by binding to the 50S subunit[13]) There is a significant variability in the relationship between the dose administered and the resultant plasma level in blood. Therapeutic drug monitoring (TDM) is necessary to obtain the correct dose. These agents exhibit a post-antibiotic effect in which there is no or very little drug level detectable in blood, but there still seems to be inhibition of bacterial re-growth. This is due to strong, irreversible binding to the ribosome, and remains intracellular long after plasma levels drop. This allows a prolonged dosage interval. Depending on their concentration, they act as bacteriostatic or bactericidal agents. The protein synthesis inhibition of aminoglycosides does not usually produce a bactericidal effect, let alone a rapid one as is frequently observed on susceptible Gram-negative bacilli. Aminoglycosides competitively displace cell biofilm-associated Mg2+ and Ca2+ that link the polysaccharides of adjacent lipopolysaccharide molecules. "The result is shedding of cell membrane blebs, with formation of transient holes in the cell wall and disruption of the normal permeability of the cell wall. This action alone may be sufficient to kill most susceptible Gramnegative bacteria before the aminoglycoside has a chance to reach the 30S ribosome." [14]

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The antibacterial properties of aminoglycosides were believed to result from inhibition of bacterial protein synthesis through irreversible binding to the 30S bacterial ribosome. This explanation, however, does not account for the potent bactericidal properties of these agents, since other antibiotics that inhibit the synthesis of proteins (such as tetracycline) are not bactericidal. Recent experimental studies show that the initial site of action is the outer bacterial membrane. The cationic antibiotic molecules create fissures in the outer cell membrane, resulting in leakage of intracellular contents and enhanced antibiotic uptake. This rapid action at the outer membrane, it is presumed, accounts for most of the bactericidal activity. Energy is needed for aminoglycoside uptake into the bacterial cell. Anaerobes have less energy available for this uptake, so aminoglycosides are less active against anaerobes. Aminoglycosides are useful primarily in infections involving aerobic, gram-negative bacteria, such as Pseudomonas, Acinetobacter, and Enterobacter. In addition, some Mycobacteria, including the bacteria that cause tuberculosis, are susceptible to aminoglycosides. The most frequent use of aminoglycosides is empiric therapy for serious infections such as septicemia, complicated intraabdominal infections, complicated urinary tract infections, and nosocomial respiratory tract infections. Usually, once cultures of the causal organism are grown and their susceptibilities tested, aminoglycosides are discontinued in favor of less toxic antibiotics. Streptomycin was the first effective drug in the treatment of tuberculosis, though the role of aminoglycosides such as streptomycin and amikacin has been eclipsed (because of their toxicity and inconvenient route of administration) except for multiple-drug-resistant strains. Infections caused by gram-positive bacteria can also be treated with aminoglycosides, but other types of antibiotics are more potent and less damaging to the host. In the past, the aminoglycosides have been used in conjunction with beta-lactam antibiotics in streptococcal infections for their synergistic effects, in particular in endocarditis. One of the most frequent combinations is ampicillin (a beta-lactam, or penicillin-related antibiotic) and gentamicin. Often, hospital staff refer to this combination as "amp and gent" or more recently called "pen and gent" for penicillin and gentamicin. Aminoglycosides are mostly ineffective against anaerobic bacteria, fungi, and viruses.
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Nonsense suppression:
The interference with DNA proofreading has been exploited to treat genetic diseases that result from premature stop codes (leading to early termination of protein synthesis and truncated proteins). Aminoglycosides can cause the cell to overcome the stop code, insert a random amino acid, and express a full-length protein. [15] The aminoglycoside gentamicin has been used to treat cystic fibrosis (CF) cells in the laboratory to induce them to grow full-length proteins. CF is caused by a mutation in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. In approximately 10% of CF cases, the mutation in this gene causes its early termination during translation, leading to the formation of is truncated and non-functional CFTR protein. It is believed that gentamicin distorts the structure of the ribosome-RNA complex, leading to a mis-reading of the termination codon, causing the ribosome to "skip" over the stop sequence and to continue with the normal elongation and production of the CFTR protein. [16]

Routes of administration
Since they are not absorbed from the gut, they are administered intravenously and intramuscularly. Some are used in topical preparations for wounds. Oral administration can be used for gut decontamination (e.g., in hepatic encephalopathy). Tobramycin may be administered in a nebulized form.

Clinical use
The recent emergence of infections due to Gram-negative bacterial strains with advanced patterns of antimicrobial resistance has prompted physicians to reevaluate the use of these antibacterial agents. [17] This revived interest in the use of aminoglycosides has brought back to light the debate on the two major issues related to these compounds, namely the spectrum of antimicrobial susceptibility and toxicity. Current evidence shows that aminoglycosides do retain activity against the majority of Gram-negative clinical bacterial isolates in many parts of the world. Still, the relatively frequent occurrence of nephrotoxicity and ototoxicity during
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aminoglycoside treatment makes physicians reluctant to use these compounds in everyday practice. Recent advances in the understanding of the effect of various dosage schedules of aminoglycosides on toxicity have provided a partial solution to this problem, although more research still needs to be done in order to overcome this problem entirely. [18]

Nomenclature
Aminoglycosides that are derived from bacteria of the Streptomyces genus are named with the suffix -mycin, whereas those that are derived from Micromonospora are named with the suffix micin. [5] This nomenclature system is not specific for aminoglycosides. For example, vancomycin is a glycopeptide antibiotic and erythromycin, which is produced from the species

Saccharopolyspora erythraea (previously misclassified as Streptomyces) along with its synthetic derivatives clarithromycin and azithromycin, is a macrolide. [7][8] All differ in their mechanisms of action, however.

Streptomycin

Neomycin

Framycetin

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Paromomycin

Ribostamycin

Kanamycin

Amikacin

Arbekacin

Bekanamycin
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Dibekacin

Tobramycin

Spectinomycin

Hygromycin B

Paromomycin sulfate

Gentamicin

Netilmicin
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Sisomicin

Isepamicin

Verdamicin

Astromicin

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Amikacin
Amikacin

Systematic (IUPAC) name

(2S)-4-amino-N-[(2S,3S,4R,5S)-5-amino-2[(2S,3R,4S,5S,6R)-4-amino-3,5-dihydroxy6-(hydroxymethyl)oxan-2-yl]oxy-4-[(2R,3R, 4S,5R,6R)-6-(aminomethyl)-3,4,5-trihydroxyoxan-2-yl]oxy-3-hydroxy-cyclohexyl]-2-hydroxybutanamide

Clinical data Trade names AHFS/Drugs.com MedlinePlus Pregnancy cat. Legal status Amikin monograph a682661 D(AU) C(US) POM (UK) -only (US) Intramuscular, intravenous

Routes

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Pharmacokinetic data Protein binding Half-life Excretion 0-11% 2-3 hours Renal Identifiers CAS number ATC code PubChem DrugBank ChemSpider UNII KEGG ChEBI ChEMBL 37517-28-5 D06AX12 J01GB06, S01AA21 CID 37768 APRD00550 34635 84319SGC3C D02543 CHEBI:2637 CHEMBL177 Chemical data Formula Mol. mass SMILES C22H43N5O13 585.603 g/mol eMolecules & PubChem

Amikacin is an aminoglycoside antibiotic used to treat different types of bacterial infections. Amikacin works by binding to the bacterial 30S ribosomal subunit, causing misreading of mRNA and leaving the bacterium unable to synthesize proteins vital to its growth.
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Administration Amikacin may be administered once or twice a day but must be given by the intravenous or intramuscular route. There is no oral form available as amikacin is not absorbed orally. In people with kidney failure, dosage must be adjusted according to the creatinine clearance, usually by reducing the dosing frequency. Uses Amikacin is most often used for treating severe, hospital-acquired infections with multidrug resistant Gram negative bacteria such as Pseudomonas aeruginosa, Acinetobacter, and Enterobacter. Serratia marcescens and Providencia stuartii are also included in the spectrum. Amikacin can also be used to treat non tubercular mycobacterial infections and tuberculosis (if caused by sensitive strains) when first line drugs fail to control the infection. Amikacin may be combined with a beta-lactam antibiotic for empiric therapy for people with neutropenia and fever. Resistance Amikacin has high resistance against bacterial inactivation. It resists attacks by most bacterial inactivating enzymes, this is accomplished by the L-hydroxyaminobuteroyl amide (L-HABA) moiety attached to N-3 which inhibits acetylation, phosphorylation and adenylation in the distant amino sugar ring (C-2,C-3,C-4). To prevent the development of bacterial resistance to this extremely powerful antibiotic, its use is tightly regulated. Side effects Side effects of amikacin are similar to other aminoglycosides. Kidney damage and hearing loss are the most important effects. Because of this potential, blood levels of the drug and markers of kidney function (creatinine) may be monitored. Moreover, doses are adjusted specifically based upon serum Creatinine clearance in clinical settings.

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Apramycin
Apramycin

Systematic (IUPAC) name

(2R,3R,4R,5S,6R)-5-amino-2- [((1R,2R,3R,4R,6R,8R)-8-amino-9- [(1R,2S,3R,4R,6R)-4,6-diamino-2,3- dihydroxycyclohexyl]oxy-2-hydroxy- 3-methylamino-5,10- dioxabicyclo[4.4.0]dec-4-yl)oxy]-6- (hydroxymethyl)oxane-3,4diol

Clinical data AHFS/Drugs.com Pregnancy cat. Legal status International Drug Names ? ? Identifiers CAS number ATCvet code PubChem DrugBank ChemSpider UNII KEGG 37321-09-8 QA07AA92 QJ01GB90 QJ51GB90 CID 3081545 DB04626 2339128 388K3TR36Z D02322

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ChEBI ChEMBL CHEBI:2790 CHEMBL1230961 Chemical data Formula Mol. mass SMILES InChI[show]

C21H41N5O11 539.58 g/mol eMolecules & PubChem

Apramycin (also Nebramycin II) is an aminoglycoside antibiotic used in veterinary medicine. It is produced by Streptomyces tenebrarius.

Pharmacology: Indication For the treatment of bacterial infections in animals. Mechanism of action Apramycin stands out among aminoglycosides for its mechanism of action which is based on blocking translocation and its ability to bind also to the eukaryotic decoding site despite differences in key residues required for apramycin recognition by the bacterial target. The drug binds in the deep groove of the RNA which forms a continuously stacked helix comprising noncanonical C.A and G.A base pairs and a bulged-out adenine. The binding mode of apramycin at the human decoding-site RNA is distinct from aminoglycoside recognition of the bacterial target, suggesting a molecular basis for the actions of apramycin in eukaryotes and bacteria.

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Arbekacin

Arbekacin

Systematic (IUPAC) name

(2S)-4-amino-N-[(1R,2S,3R,4R,5S)-5-amino-2-{[(2S,3R,4S,5S,6R)-4-amino-3,5-dihydroxy-6(hydroxymethyl)oxan-2-yl]oxy}-4-{[(2R,3R,6S)-3-amino-6-(aminomethyl)oxan-2-yl]oxy}-3-hydroxycyclohexyl]2-hydroxybutanamide

Clinical data

AHFS/Drugs.com

International Drug Names

Pregnancy cat.

? Prescription only

Legal status

Routes

Intramuscular, intravenous Pharmacokinetic data

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Metabolism Minimal

Excretion

Renal

Identifiers

CAS number

51025-85-5

ATC code

J01GB12

PubChem

CID 11398765

DrugBank

DB06696

ChemSpider

2140

UNII

G7V6SLI20L

KEGG

D07462

ChEMBL

CHEMBL233430

Chemical data

Formula

C22H44N6O10 552.62 g/mol

Mol. mass

Arbekacin (INN) is a semisynthetic aminoglycoside antibiotic. It is primarily used for the treatment of infections caused by multi-resistant bacteria including methicillin-resistant
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Staphylococcus aureus (MRSA), Arbekacin was originally synthesized from dibekacin in 1973. It has been registered and marketed in Japan since 1990 under the trade name Habekacin. Arbekacin is no longer covered by patent and generic versions of the drug are also available under such trade names as Decontasin and Blubatosine. Pharmacology: Indication Arbekacin is used for the short term treatment of multi-resistant bacterial infections, such as methicillin-resistant Staphylococcus aureus (MRSA). Pharmacodynamics Aminoglycosides, such as Arbekacin, work by binding to the bacterial 30S ribosomal subunit, causing misreading of t-RNA which consequently, leaves the bacterium unable to synthesize proteins vital to its growth. Energy is needed for aminoglycoside uptake into the bacterial cell. Anaerobes have less energy available for this uptake, so aminoglycosides are less active against anaerobes. Aminoglycosides are useful primarily in infections involving aerobic, gram-negative bacteria, such as Pseudomonas, Acinetobacter, and Enterobacter. Mechanism of action Aminoglycosides, such as 'Arbekacin, inhibit protein synthesis in susceptible bacteria by irreversibly binding to bacterial 30S and 16S ribosomal subunits. Specifically Arbekacin binds to four nucleotides of 16S rRNA and a single amino acid of protein S12. This interferes with decoding site in the vicinity of nucleotide 1400 in 16S rRNA of 30S subunit. This region interacts with the wobble base in the anticodon of tRNA. This leads to misreading of mRNA so incorrect amino acids are inserted into the polypeptide leading to nonfunctional or toxic peptides and the breakup of polysomes into nonfunctional monosomes.

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Absorption Aminoglycosides are not well absorbed from the gastrointestinal tract. Their absorption is markedly improved by parenteral administration. Toxicity Ototoxicity and nephrotoxicity are the most serious adverse effects of aminoglycoside therapy and are more likely to occur in patients with a history of renal impairment or who are receiving other ototoxic and/or nephrotoxic drugs. Normal duration of IM or IV aminoglycoside therapy is 7-10 days. Although a longer duration may be necessary in some cases, toxicity is more likely to occur when aminoglycoside treatment is continued for longer than 10 days. Affected organisms Enteric bacteria and other eubacteria

Gentamicin

Gentamicin

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Systematic (IUPAC) name

(3R,4R,5R)-2-{[(1S,2S,3R,4S,6R)-4,6diamino-3-{[(2R,3R,6S)3-amino-6-[(1R)1-(methylamino)ethyl]oxan-2-yl]oxy}2-hydroxycyclohexyl]oxy}-5-methyl4-(methylamino)oxane-3,5-diol

Clinical data AHFS/Drugs.com MedlinePlus Pregnancy cat. Legal status Routes monograph a682275 D POM (UK) IV, IM, topical Pharmacokinetic data Bioavailability Protein binding Half-life Excretion limited oral bioavailability 0-10% 2 hrs Renal

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Identifiers CAS number ATC code 1403-66-3 D06AX07 J01GB03 S01AA11 S02AA14 S03AA06 QA07AA91 QG01AA91 QG51AA04 QJ51GB03 CID 3467 2427 DB00798 390067 T6Z9V48IKG D08013 CHEBI:27412 CHEMBL195892 Chemical data Formula Mol. mass SMILES InChI[show]

PubChem IUPHAR ligand DrugBank ChemSpider UNII KEGG ChEBI ChEMBL

C21H43N5O7 477.596 g/mol eMolecules & PubChem

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Gentamicin is an aminoglycoside antibiotic, used to treat many types of bacterial infections, particularly those caused by Gram-negative organisms. However, gentamicin is not used for Neisseria gonorrhoeae, Neisseria meningitidis or Legionella pneumophila. Gentamicin is also ototoxic and nephrotoxic, with this toxicity remaining a major problem in clinical use.
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It is synthesized by Micromonospora, a genus of Gram-positive bacteria widely present in the environment (water and soil). To highlight their specific biological origins, gentamicin and other related antibiotics produced by this genus (verdamicin, mutamicin, sisomicin, netilmicin, retymicin) generally have their spellings ending in ~micin and not in ~mycin. Gentamicin is a bactericidal antibiotic that works by binding the 30S subunit of the bacterial ribosome, interrupting protein synthesis. Like all aminoglycosides, when gentamicin is given orally, it is not systemically active. This is because it is not absorbed to any appreciable extent from the small intestine. It is administered intravenously, intramuscularly or topically to treat infections. It appears to be completely eliminated unchanged in the urine. Urine must be collected for many days to recover all of a given dose because the drug binds avidly to certain tissues. E. coli has shown some resistance to gentamicin, despite being Gram-negative. Reluctance to use gentamicin for empirical therapy has led to increased use of alternative broad-spectrum antibiotics, which some experts suggest has led to the prevalence of antibiotic-resistant bacterial infections by Golden Staph and other so-called "superbugs". Gentamicin is one of the few heat-stable antibiotics that remain active even after autoclaving, which makes it particularly useful in the preparation of some microbiological growth media. It is used during orthopaedic surgery when high temperatures are required for the setting of cements (e.g. hip replacements).

Spectrum of activity Active against a wide range of human bacterial infections, mostly Gram-negative bacteria including Pseudomonas, Proteus, Serratia, and the Gram-positive Staphylococcus. Gentamicin is not used for Neisseria gonorrhoeae, Neisseria meningitidis or Legionella pneumophila bacterial infections (because of the risk of the patient going into shock from lipid A endotoxin found in

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certain Gram-negative organisms). Gentamicin is also useful against Yersinia pestis and its relatives. Side effects These aminoglycosides are toxic to the sensory cells of the ear, but they vary greatly in their relative effects on hearing versus balance. Gentamicin is a vestibulotoxin, and can cause permanent loss of equilibrioception, caused by damage to the vestibular apparatus of the inner ear, usually if taken at high doses or for prolonged periods of time, but there are well documented cases in which gentamicin completely destroyed the vestibular apparatus after three to five days. A small number of affected individuals have a normally harmless mutation in their mitochondrial RNA (m1555 A>G), that allows the gentamicin to affect their cells. The cells of the ear are particularly sensitive to this, sometimes causing complete hearing loss. However, gentamicin is sometimes used intentionally for this purpose in severe Mnire's disease, to disable the vestibular apparatus. Gentamicin can also be highly nephrotoxic, particularly if multiple doses accumulate over a course of treatment. For this reason gentamicin is usually dosed by body weight. Various formulae exist for calculating gentamicin dosage. Also trough and peak serum levels of gentamicin are monitored during treatment, generally before and after the third dose is infused. Gentamicin, like other aminoglycosides, causes nephrotoxicity by inhibiting protein synthesis in renal cells. This mechanism specifically causes necrosis of cells in the proximal tubule, resulting in acute tubular necrosis which can lead to acute renal failure. Side effects of gentamicin toxicity vary from patient to patient. Side effects may become apparent shortly after or up to months after gentamicin is administered. Symptoms of gentamicin toxicity include:

Balance difficulty Bouncing, unsteady vision Ringing in the ears (tinnitus) Difficulty multi-tasking, particularly when standing
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Psychiatric symptoms related to gentamicin can occur. These include anorexia, confusion, depression, disorientation and visual hallucinations. Immediate professional help should be sought if any of these symptoms or others appear after administration of aminoglycosides. General medical practitioners should refer patients with such symptoms to an otolaryngologist, commonly known as an 'ear, nose, and throat doctor', for comprehensive tests. A number of factors and determinants should be taken into account when using gentamicin, including differentiation between empirical and directed therapy which will affect dosage and treatment period. Many medical practitioners freely administer gentamicin as an antibiotic without advising patients of the severe and permanent potential ramifications of its use. Gentamicin is well known to be a cheap, low cost yet old medicine as compared to modern alternatives, and is typically US$36 per dosage less than modern alternatives. Many people recover from gentamicin toxicity naturally over time if the drug is discontinued, but they recover slowly and usually incompletely. Sometimes the toxicity of gentamicin can still increase over months after the last dose. Upon cessation of gentamicin therapy symptoms such as tinnitus and imbalance may become less pronounced. Sensori-neural hearing loss caused by gentamicin toxicity is permanent however. Production and usage in research Gentamicin is produced by a fermentation procedure. It was discovered by a Chinese microbiologist, Yue Wang. The majority of the world's gentamicin production takes place in China and South Korea; the last European producer is Lek, part of Sandoz group. Gentamicin has been used since the early 1980s in microbiological research. The gentamicin protection assay enables researchers to quantify the ability of pathogenic bacteria to invade eukaryotic cells. It takes advantage of the fact that gentamicin is not able to penetrate eukaryotic cells.

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Kanamycin

Kanamycin

Systematic (IUPAC) name

2-(aminomethyl)- 6-[4,6-diamino-3- [4-amino-3,5-dihydroxy-6-(hydroxymethyl) tetrahydropyran-2-yl]oxy- 2hydroxy- cyclohexoxy]- tetrahydropyran- 3,4,5-triol

Clinical data AHFS/Drugs.com Pregnancy cat. Legal status Routes monograph D ? Oral, intravenous, intramuscular Pharmacokinetic data Bioavailability Metabolism Half-life Excretion very low after oral delivery Unknown 2 hours 30 minutes Urine (as unchanged drug) Identifiers

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CAS number ATC code PubChem DrugBank ChemSpider UNII ChEBI ChEMBL 59-01-8 A07AA08 J01GB04 S01AA24 CID 6032 APRD00026 5810 RUC37XUP2P CHEBI:17630 CHEMBL1384 Chemical data Formula Mol. mass SMILES InChI[show]

C18H36N4O11 484.499 eMolecules & PubChem

(what is this?) (verify)

Kanamycin sulfate is an aminoglycoside antibiotic, available in oral, intravenous, and intramuscular forms, and used to treat a wide variety of infections. Kanamycin is isolated from Streptomyces kanamyceticus.

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Mechanism Kanamycin interacts with the 30S subunit of prokaryotic ribosomes. It induces substantial amounts of mistranslation and indirectly inhibits translocation during protein synthesis. Side effects Serious side effects include tinnitus or loss of hearing, toxicity to kidneys, and allergic reactions to the drug. Use in research Kanamycin is used in molecular biology as a selective agent most commonly to isolate bacteria (e.g., E. coli) which have taken up genes (e.g., of plasmids) coupled to a gene coding for kanamycin resistance (primarily Neomycin phosphotransferase II [NPT II/Neo]). Bacteria that have been transformed with a plasmid containing the kanamycin resistance gene are plated on kanamycin (50-100 ug/ml) containing agar plates or are grown in media containing kanamycin (50-100 ug/ml). Only the bacteria that have successfully taken up the kanamycin resistance gene become resistant and will grow under these conditions. As a powder kanamycin is white to offwhite and is soluble in water (50 mg/ml). Mammalian cells and other eukaryotes are screened using G418, a similar aminoglycoside antibiotic, which KanMX confers resistance against. At least one such gene, Atwbc19 is native to a plant species, of comparatively large size and its coded protein acts in a manner which decreases the possibility of Horizontal Gene Transfer from the plant to bacteria; it may be incapable of giving resistance to kanamycin to bacteria even if gene transfer occurs.

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Neomycin
Neomycin

Systematic (IUPAC) name

(1R,2R,3S,4R,6S)-4,6-diamino-2-

Clinical data Trade names AHFS/Drugs.com MedlinePlus Pregnancy cat. Legal status Routes Neo-rx monograph a682274 ? OTC Topical, Oral Pharmacokinetic data

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Half-life 2 to 3 hours Identifiers CAS number ATC code 1404-04-2 A01AB08 A07AA01, B05CA09, D06AX04, J01GB05, R02AB01, S01AA03, S02AA07, S03AA01 PubChem IUPHAR ligand DrugBank ChemSpider UNII KEGG ChEBI ChEMBL CID 8378 709 DB00994 8075 I16QD7X297 D08260 CHEBI:7508 CHEMBL449118 Chemical data Formula Mol. mass SMILES InChI[show]

C23H46N6O13 614.644 g/mol eMolecules & PubChem

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Neomycin is an aminoglycoside antibiotic that is found in many topical medications such as creams, ointments, and eyedrops. The discovery of Neomycin dates back to 1949. It was discovered in the lab of Selman Waksman, who was later awarded the Nobel Prize in Physiology and medicine in 1951. Neomycin, belongs to aminoglycoside class of antibiotics which contain two or more aminosugars connected by glycosidic bonds. Neamine (two rings), Ribostamycin (three rings), Paromomycin (four rings) and Lividomycin (five rings) are some other examples of aminoglycosides. They have shown tremendous potential as antibacterials. One of them, Gentamicin has been used extensively in clinical practice. Due to the inherent oto and nephrotoxicity of these substances, systemic use has declined as safer alternatives have become available. Uses Neomycin is overwhelmingly used as a topical preparation, such as Neosporin. It can also be given orally, where it is usually combined with other antibiotics. Neomycin is not absorbed from the gastrointestinal tract and has been used as a preventive measure for hepatic encephalopathy and hypercholesterolemia. By killing bacteria in the intestinal tract, it keeps ammonia levels low and prevents hepatic encephalopathy, especially prior to GI surgery. It has also been used to treat small intestinal bacterial overgrowth. It is not given intravenously, as neomycin is extremely nephrotoxic (causes kidney damage), especially compared to other aminoglycosides. The exception is when neomycin is included, in very small quantities, as a preservative in some vaccines - typically 0.025 mg per dose. Molecular biology Neomycin resistance is conferred by either one of two aminoglycoside phosphotransferase genes. A neo gene is commonly included in DNA plasmids used by molecular biologists to establish stable mammalian cell lines expressing cloned proteins in culture; many commercially available protein expression plasmids contain neo as a selectable marker. Non-transfected cells will eventually die off when the culture is treated with neomycin or similar antibiotic. Neomycin or kanamycin can be used for prokaryotes, but geneticin (G418) is, in general, needed for eukaryotes.
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Spectrum Similar to other aminoglycosides, neomycin has excellent activity against Gram-negative bacteria, and has partial activity against Gram-positive bacteria. It is relatively toxic to humans, and many people have allergic reactions to it. See: Hypersensitivity. Physicians sometimes recommend using antibiotic ointments without neomycin, such as Polysporin. History Neomycin was discovered in 1949 by the microbiologist Selman Waksman and his student Hubert Lechevalier at Rutgers University. It is produced naturally by the bacterium Streptomyces fradiae. Neomycin as a DNA binder Neomycin belongs to the family of aminoglycosides. This family includes many other medicinally important drugs: streptomycin, paromomycin and kanamycin . Aminoglycosides are known for their ability to bind to duplex RNA with high affinity. A study done by Daniel Pilch, Associate Professor Dept. of Pharmacology at Rutgers University, and his coworkers determined the association constant for neomycin with A-site RNA was found to be in the ~109 range. However, more than 50 years after its discovery, its DNA-binding properties were still unknown. In 2000, Dev P. Arya, currently Director of the Laboratory of Medicinal Chemistry at Clemson University, and his coworkers discovered that neomycin induces enormous thermal stabilization of triplex DNA while having little or almost no effect on the DNA duplex stabilization. They also showed that neomycin binds to structures that adopt A-form structure, triplex DNA being one of them. They later went on to show that neomycin even induces DNA:RNA hybrid triplex formation.

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Netilmicin

Netilmicin

Systematic (IUPAC) name

(2R,3R,4R,5R)-2-{[(1S,2S,3R,4S,6R)-4-amino-3-{[(2S,3R)-3-amino-6-(aminomethyl)-3,4-dihydro-2H-pyran-2yl]oxy}-6-(ethylamino)-2-hydroxycyclohexyl]oxy}-5-methyl-4-(methylamino)oxane-3,5-diol

Clinical data AHFS/Drugs.com MedlinePlus Pregnancy cat. Legal status monograph a605011 ? ? Pharmacokinetic data Bioavailability Half-life ~0% 2.5 hours

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Identifiers CAS number ATC code PubChem DrugBank ChemSpider UNII KEGG ChEMBL 56391-56-1 J01GB07 S01AA23 CID 41859 APRD00232 38195 4O5J85GJJB D08268 CHEMBL1572 Chemical data Formula Mol. mass SMILES InChI[show]

C21H41N5O7 475.58 g/mol eMolecules & PubChem

(what is this?) (verify)

Netilmicin is a member of the aminoglycoside family of antibiotics. These antibiotics have the ability to kill a wide variety of bacteria. Netilmicin is not absorbed from the gut and is therefore only given by injection or infusion. It is only used in the treatment of serious infections particularly those resistant to gentamicin.

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Available dosage forms Available dosage forms include:

UK: netilmicin (as Sulphate):

o o o

10 mg/mL (1.5 mL amp) 50 mg/mL (1-mL amp) 100 mg/mL(1-mL,1.5-mL & 2-mL amp)

France: Ntilmicin sulfate:

o o o o

Amp 25 mg/1 mL 50 mg/2 mL 100 mg/1 mL 150 mg/1.5 mL

Ingredients for 100 mg/mL vial Netilmicin (as sulphate) 100 mg Sodium metabisulfite Sodium sulfite Edetate disodium Benzyl alcohol Water for injection 2.4 mg 0.8 mg 0.1 mg 10 mg qs 1 mL

FDA approval date : February 28, 1983

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Comparison with drugs of the same therapeutic category: According to the British National Formulary (BNF), netilmicin has similar activity to gentamicin, but less ototoxicity in those needing treatment for longer than 10 days.Netilmicin is active against a number of gentamicin-resistant Gram-negative bacilli but is less active against Ps. Aeuroginosa than gentamicin or tobramycin. However according to the below-mentioned studies, the above advantages are somehow controversial:

Netilmicin

(Netromycin,

Schering-Plough,

Netspan-

Cipla):

In summary, netilmicin has not been demonstrated to have significant advantages over other aminoglycosides (gentamicin, tobramycin, amikacin), and it is more expensive; thus, its potential value is limited. Drug Intelligence & Clinical Pharmacy: Vol. 17, No. 2, pp. 83-91.

Once-daily gentamicin versus once-daily netilmicin in patients with serious infectionsa randomized clinical trial:

We conclude that with once-daily dosing no benefit of netilmicin over gentamicin regarding nephro- or ototoxicity could be demonstrated. Journal of Antimicrobial Chemotherapy (1994) 33, 823-835.

Ototoxicity and nephrotoxicity of gentamicin vs netilmicin in patients with serious infections. A randomized clinical trial:

We conclude that with once-daily treatment no benefit of netilmicin over gentamicin regarding nephro- or ototoxicity could be demonstrated. Clin Otolaryngol Allied Sci. 1995 Apr;20(2):118-23.

Relative efficacy and toxicity of netilmicin and tobramycin in oncology patients: We conclude that aminoglycoside-associated ototoxicity was less severe and more often reversible with netilmicin than with tobramycin. Arch Intern Med. 1986 Dec;146(12):232934.

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Daily single-dose aminoglycoside administration. Therapeutic and economic benefits: Animal studies have shown that dosing aminoglycosides once daily is more efficient and less nephrotoxic than the conventional multiple daily dosing regimens. Netilmicin and amikacin are the drugs most often used in clinical trials of once-daily dosing regimens. Ugeskr Laeger. 1993 May 10;155(19):1436-41.

Comparison of Netilmicin with Gentamicin in the Therapy of Experimental Escherichia coli Meningitis: Because of its reduced toxicity and greater in vivo bactericidal activity, netilmicin may offer an advantage over gentamicin in the therapy of gram-negative bacillary meningitis. Antimicrob Agents Chemother. 1978 June; 13(6): 899-904.

A comparison of netilmicin and gentamicin in the treatment of pelvic infections: The microbacteria isolated by standard culture techniques before therapy revealed Neisseria gonorrhoeae in 69% and 51% of the netilmicin and gentamicin groups, respectively; anaerobic organisms were cultured in about 75% of each group. Obstetrics & Gynecology 1979;54:554-557.

Netilmicin:

review

of

toxicity

in

laboratory

animals:

Presently available data suggest that netilmicin offers distinct advantages over older aminoglycosides. Final conclusions must await prospective randomized double-blind trials in man. J Int Med Res. 1978;6(4):286-99.

Nonparallel

nephrotoxicity

dose-response

curves

of

aminoglycosides:

Nephrotoxicity comparisons of aminoglycosides in rats, utilizing large multiples of human doses, have indicated an advantage for netilmicin. However, no nephrotoxicity advantage of netilmicin has been demonstrated at the lower doses used in clinics. Antimicrob Agents Chemother. 1981 June; 19(6): 10241028.

Comparative

ototoxicity

of

netilmicin,

gentamicin,

and

tobramycin

in

cats:

Under the conditions of this study, at least a twofold (vestibular) to fourfold (cochlear) relative safety margin for ototoxicity was established in favor of netilmicin over tobramycin and gentamicin. Toxicol Appl Pharmacol. 1985 Mar 15;77(3):479-89.
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Comparison

of

Netilmicin

and

Gentamicin

Pharmacokinetics

in

Humans:

In a crossover study, single doses of netilmicin and gentamicin were administered intramuscularly, each at 1.0 and 2.5 mg/kg. No significant differences were observed between the two drugs in disposition half-life, rate of distribution and elimination, area under the serum concentration-time curve, urinary excretion, total body clearance, and renal clearance. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Feb. 1980, p. 184-187. Schering-Plough Research Division, Bloomfield, New Jersey 07003.

Paromomycin sulfate

Paromomycin

Systematic (IUPAC) name

(2R,3S,4R,5R,6S)-5-amino-6-[(1R,2S,3S,4R,6S)4,6-diamino-2-[(2S,3R,4R,5R)-4-[(2R,3R,4R,5R,6S)3-amino-6-(aminomethyl)-4,5-dihydroxy-oxan-2-yl] oxy-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy3-hydroxy-cyclohexyl]oxy-2-(hydroxymethyl)oxane-3,4-diol

Clinical data

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AHFS/Drugs.com MedlinePlus Pregnancy cat. Legal status Routes monograph a601098 B(US) Rx only U.S. Oral, intramuscular Pharmacokinetic data Bioavailability Metabolism Half-life Excretion None None ? Fecal Identifiers CAS number ATC code PubChem DrugBank ChemSpider ChEMBL 1263-89-4 A07AA06 CID 441375 DB01421 390117 CHEMBL370143 Chemical data

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Aminoglycoside
Formula Mol. mass SMILES C23H47N5O18S 615.629 g/mol eMolecules & PubChem

Paromomycin (brand name Humatin) is an aminoglycoside antibiotic, first isolated from Streptomyces krestomuceticus in the 1950s. It is also called monomycin and aminosidine; Uses It is an antibiotic designed to fight intestinal infections such as cryptosporidiosis, amoebiasis, and leishmaniasis. The route of administration is intramuscular injection and capsule. Mechanism Paromomycin inhibits protein synthesis by binding to 16S ribosomal RNA. History and availability Paromomycin was demonstrated to be effective against cutaneous leishmaniasis in clinical studies in the USSR in the 1960s, and in trials with visceral leishmaniasis in the early 1990s. It was developed as a therapeutic against visceral leishmaniasis by the Institute for OneWorld Health. Paromomycin was granted orphan drug status in 2005 and was approved by the Drug Controller General of India in September 2006 for treatment of visceral leishmaniasis. As of February 5th, 2008, King Pharmaceuticals is discontinuing the sale of Humatin. Paromomycin continues to be available in the United States from another manufacturer.[9]

Streptomycin
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Streptomycin

Systematic (IUPAC) name

5-(2,4-diguanidino3,5,6-trihydroxy-cyclohexoxy)- 4-[4,5-dihydroxy-6-(hydroxymethyl) -3-methylamino-tetrahydropyran-2-yl] oxy-3-hydroxy-2-methyl -tetrahydrofuran-3-carbaldehyde

Clinical data AHFS/Drugs.com Pregnancy cat. Legal status Routes monograph DM[1] POM (UK) -only (US)

Intramuscular, intravenous Pharmacokinetic data

Bioavailability

84% to 88% (est.)[2]

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Half-life Excretion 5 to 6 hours Renal Identifiers CAS number ATC code PubChem DrugBank ChemSpider UNII KEGG ChEBI ChEMBL 57-92-1 A07AA04 J01GA01 CID 19649 DB01082 18508 Y45QSO73OB D08531 CHEBI:17076 CHEMBL1201194 Chemical data Formula Mol. mass SMILES C21H39N7O12 581.574 g/mol eMolecules & PubChem Physical data Melt. point 12 C (54 F) (what is this?) (verify)

Streptomycin is an antibiotic drug, the first of a class of drugs called aminoglycosides to be discovered, and was the first antibiotic remedy for tuberculosis. It is derived from the actinobacterium Streptomyces griseus. Streptomycin is a bactericidal antibiotic. Streptomycin
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Aminoglycoside
cannot be given orally, but must be administered by regular intramuscular injections. An adverse effect of this medicine is ototoxicity. Mechanism of action Streptomycin is a protein synthesis inhibitor. It binds to the small 16S 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. Humans have structurally different ribosomes from bacteria, thereby allowing the selectivity of this antibiotic for bacteria. However at low concentrations 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 a 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 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; 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 (18871982). 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

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

Tobramycin
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Tobramycin

Systematic (IUPAC) name

(2S,3R,4S,5S,6R)-4-amino-2-{[(1S,2S,3R,4S,6R)-4,6-diamino-3-{[(2R,3R,5S,6R)-3-amino-6-(aminomethyl)-5hydroxyoxan-2-yl]oxy}-2-hydroxycyclohexyl]oxy}-6-(hydroxymethyl)oxane-3,5-diol

Clinical data Trade names AHFS/Drugs.com MedlinePlus Pregnancy cat. Legal status Routes Tobrex monograph a682660 D (Injection, Inhalation); B (Ophthalmic) (US) ? IV, IM, inhalation, ophthalmic Pharmacokinetic data

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Protein binding < 30% Identifiers CAS number ATC code PubChem DrugBank ChemSpider UNII KEGG ChEBI ChEMBL 32986-56-4 J01GB01 S01AA12 CID 36294 APRD00582 33377 VZ8RRZ51VK D00063 CHEBI:28864 CHEMBL1747 Chemical data Formula Mol. mass SMILES InChI[show]

C18H37N5O9 467.515 g/mol eMolecules & PubChem

(what is this?) (verify)

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Tobramycin is an aminoglycoside antibiotic used to treat various types of bacterial infections, particularly Gram-negative infections. Mechanism of action Tobramycin works by binding to a site on the bacterial 30S and 50S ribosome, preventing formation of the 70S complex. As a result, mRNA cannot be translated into protein and cell death ensues. Tobramycin is preferred over gentamicin for Pseudomonas aeruginosa pneumonia due to better lung penetration and bactericidal activity. Administration Like all aminoglycosides, tobramycin does not pass the gastro-intestinal tract, so for systemic use it can only be given intravenously, intramuscularly, eyedrops (commonly with Dextramethsone), or it can be administered and inhaled via nebuliser. The formulation for injection is branded Nebcin. Patients with cystic fibrosis will often take an inhalational (nebulised) form (Tobi) for suppression of Pseudomonas aeruginosa infections. Tobramycin is also combined with dexamethasone as an ophthalmic solution (TobraDex). Bausch & Lomb Pharmaceuticals produces a sterile tobramycin solution (eye-drops) with a tobramycin concentration of 0.3%, which is available by prescription only in the United States and Canada. (In some countries, such as Italy, it is available over the counter.) It is mixed with 0.01% benzalkonium chloride as a preservative. These concentrations result in 3 mg per ml and 0.1 mg per ml, respectively. A proprietary formulation of micronized, nebulized tobramycin has been tested as a treatment for bacterial sinusitis. Side effects Like other aminoglycosides, tobramycin can cause deafness or a loss of equilibrioception (vertigo) in genetically susceptible individuals. These individuals have a normally harmless mutation in their DNA, that allows the tobramycin to affect their cells. The cells of the ear are particularly sensitive to this.
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Tobramycin can also be highly toxic to the kidneys, particularly if multiple doses accumulate over a course of treatment. For these reasons, when tobramycin is given parenterally, it is usually dosed by body weight. Various formulae exist for calculating tobramycin dosage. Also serum levels of tobramycin are monitored during treatment.

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References
1. ^ MeSH Aminoglycosides 2. ^ "Bacterial 'battle for survival' leads to new antibiotic" (Press release). Massachusetts Institute of Technology. February 26, 2008. http://web.mit.edu/newsoffice/2008/antibiotics-0226.html. Retrieved December 1, 2010. 3. ^ Ryden, R; Moore (1977). "BJ". J Antimicrob Chemother 3 (6): 609613. 4. ^ Kroppenstedt RM, Mayilraj S, Wink JM (Jun 2005). "Eight new species of the genus Micromonospora, Micromonospora citrea sp. nov., Micromonospora echinaurantiaca sp. nov., Micromonospora echinofusca sp. nov. Micromonospora fulviviridis sp. nov., Micromonospora inyonensis sp. nov., Micromonospora peucetia sp. nov., Micromonospora sagamiensis sp. nov., and Micromonospora viridifaciens sp. nov". Syst Appl Microbiol. 28 (4): 32839. PMID 15997706. 5. ^ Paul M. Dewick (2009). Medicinal Natural Products: A Biosynthetic Approach (3rd ed ed.). Wiley. ISBN 0470741678. 6. ^ Walter P. Hammes1 and Francis C. Neuhaus (1974). On the Mechanism of Action of Vancomycin: Inhibition of Peptidoglycan Synthesis in Gaffkya homari. 6. pp. 722728. 7. ^ Protein synthesis inhibitors: macrolides mechanism of action animation. Classification of agents Pharmamotion. Author: Gary Kaiser. The Community College of Baltimore County. Retrieved on July 31, 2009 8. ^ The Mechanism of Action of Macrolides, Lincosamides and Streptogramin B Reveals the Nascent Peptide Exit Path in the Ribosome Martin Lovmar and Mns Ehrenberg 9. ^ a b Pharmamotion --> Protein synthesis inhibitors: aminoglycosides mechanism of action animation. Classification of agents Posted by Flavio Guzmn on 12/08/08 10. ^ Shakil, Shazi; Khan, Rosina; Zarrilli, Raffaele; Khan, Asad U. (2007). "Aminoglycosides versus bacteria a description of the action, resistance mechanism, and nosocomial battleground". Journal of Biomedical Science 15 (1): 514. doi:10.1007/s11373-007-9194-y. PMID 17657587. 11. ^ Levison, Matthew E. (July 2009). "Aminoglycosides: Bacteria and Antibacterial Drugs". Merck Manual Professional. http://www.merck.com/mmpe/sec14/ch170/ch170b.html.
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12. ^ "Aminoglycosides". http://www.aic.cuhk.edu.hk/web8/aminoglycosides.htm. 13. ^ Champney, W. S. (2001). "Bacterial Ribosomal Subunit Synthesis A Novel Antibiotic Target". Current Drug Targets - Infectious Disorders 1 (1): 1936. doi:10.2174/1568005013343281. PMID 12455231. 14. ^ Lorian, Victor (1996). Antibiotics in Laboratory Medicine. Williams & Wilkins Press. pp. 58990. ISBN 0-683-05169-5. 15. ^ Feero, W. Gregory; Guttmacher, Alan E.; Dietz, Harry C. (2010). "New Therapeutic Approaches to Mendelian Disorders". New England Journal of Medicine 363 (9): 852 63. doi:10.1056/NEJMra0907180. PMID 20818846. 16. ^ Wilschanski, Michael; Yahav, Yaacov; Yaacov, Yasmin; Blau, Hannah; Bentur, Lea; Rivlin, Joseph; Aviram, Micha; Bdolah-Abram, Tali et al. (2003). "Gentamicin-Induced Correction of CFTR Function in Patients with Cystic Fibrosis andCFTRStop Mutations". New England Journal of Medicine 349 (15): 143341. doi:10.1056/NEJMoa022170. PMID 14534336. 17. ^ Falagas, Matthew E; Grammatikos, Alexandros P; Michalopoulos, Argyris (2008). "Potential of old-generation antibiotics to address current need for new antibiotics". Expert Review of Anti-infective Therapy 6 (5): 593600. doi:10.1586/14787210.6.5.593. PMID 18847400.
18.

^ Durante-Mangoni, Emanuele; Grammatikos, Alexandros; Utili, Riccardo; Falagas, Matthew E. (2009). "Do we still need the aminoglycosides?". International Journal of Antimicrobial Agents 33 (3): 2015. doi:10.1016/j.ijantimicag.2008.09.001. PMID 18976888.

External links

MedlinePlus drug information - Aminoglycosides (Systemic) Science Daily Bacterial 'Battle for Survival' - Rhodostreptomycin

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