Aminoglycoside

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Streptomycin. 2D line-angle representation. Streptomycin2.svg
Streptomycin. 2D line-angle representation.

Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside (sugar). [1] [2] The term can also refer more generally to any organic molecule that contains amino sugar substructures. Aminoglycoside antibiotics display bactericidal activity against Gram-negative aerobes and some anaerobic bacilli where resistance has not yet arisen but generally not against Gram-positive and anaerobic Gram-negative bacteria. [3]

Contents

Streptomycin is the first-in-class aminoglycoside antibiotic. It is derived from Streptomyces griseus and is the earliest modern agent used against tuberculosis. Streptomycin lacks the common 2-deoxystreptamine moiety (image right, below) present in most other members of this class. Other examples of aminoglycosides include the deoxystreptamine-containing agents kanamycin, tobramycin, gentamicin, and neomycin (see below).

2-deoxystrept-amine, 2D representation, oxygens, nitrogens (with attached hydrogens) in red, blue. 2deoxystreptamine.png
2-deoxystrept-amine, 2D representation, oxygens, nitrogens (with attached hydrogens) in red, blue.

Nomenclature

Aminoglycosides that are derived from bacteria of the Streptomyces genus are named with the suffix -mycin, whereas those that are derived from Micromonospora [4] are named with the suffix -micin. [5] However, this nomenclature system is not specific for aminoglycosides, and so appearance of this set of suffixes does not imply common mechanism of action. (For instance, vancomycin, a glycopeptide antibiotic, [6] and erythromycin, [7] a macrolide antibiotic produced by Saccharopolyspora erythraea , along with its synthetic derivatives clarithromycin and azithromycin, all share the suffixes but have notably different mechanisms of action.)

In the following gallery, kanamycin A to netilmicin are examples of the 4,6-disubstituted deoxystreptamine sub-class of aminoglycosides, the neomycins are examples of the 4,5-disubstituted sub-class, and streptomycin is an example of a non-deoxystreptamine aminoglycoside. [2]

Mechanisms of action

Streptomycin in complex with a bacterial ribosome. X-ray crystallographic structure of the 30S ribosomal subunit with bound drug (purple, space-filling model, at center) protein secondary structure elements such as alpha-helices in bright green, and the RNA phosphodiester backbone shown in orange (and the ladder of base pairs in dark green and blue) 30S streptomycin complex.png
Streptomycin in complex with a bacterial ribosome. X-ray crystallographic structure of the 30S ribosomal subunit with bound drug (purple, space-filling model, at center) protein secondary structure elements such as alpha-helices in bright green, and the RNA phosphodiester backbone shown in orange (and the ladder of base pairs in dark green and blue)

Aminoglycosides display concentration-dependent bactericidal activity against "most gram-negative aerobic and facultative anaerobic bacilli" but not against gram-negative anaerobes and most gram-positive bacteria. [3] They require only short contact time, and are most effective against susceptible bacterial populations that are rapidly multiplying. [8] These activities are attributed to a primary mode of action as protein synthesis inhibitors, though additional mechanisms are implicated for some specific agents, and/or thorough mechanistic descriptions are as yet unavailable. [2] [3] [8]

The inhibition of protein synthesis is mediated through aminoglycosides' energy-dependent, sometimes irreversible binding, to the cytosolic, membrane-associated bacterial ribosome (image at right). [2] (Aminoglycosides first cross bacterial cell walls—lipopolysaccharide in gram-negative bacteria—and cell membranes, where they are actively transported. [8] ) While specific steps in protein synthesis affected may vary somewhat between specific aminoglycoside agents, as can their affinity and degree of binding, [8] aminoglycoside presence in the cytosol generally disturbs peptide elongation at the 30S ribosomal subunit, giving rise to inaccurate mRNA translation and therefore biosynthesis of proteins that are truncated, or bear altered amino acid compositions at particular points. [2] Specifically, binding impairs translational proofreading leading to misreading of the RNA message, premature termination, or both, and so to inaccuracy of the translated protein product. The subset of aberrant proteins that are incorporated into the bacterial cell membrane may then lead to changes in its permeability and then to "further stimulation of aminoglycoside transport". [2] The amino sugar portion of this class of molecules (e.g., the 2-deoxystreptamine in kanamycins, gentamicins, and tobramycin, see above) are implicated in the association of the small molecule with ribosomal structures that lead to the infidelities in translation (ibid.). Inhibition of ribosomal translocation—i.e., movement of the peptidyl-tRNA from the A- to the P-site—has also been suggested[ citation needed ]. Recent single-molecule tracking experiments in live E. coli showed an ongoing but slower protein synthesis upon treatment with different aminoglycoside drugs. [9] (Spectinomycin, a related but distinct chemical structure class often discussed with aminoglycosides, does not induce mRNA misreading and is generally not bactericidal.) [8]

It has been proposed that aminoglycoside antibiotics cause oxidation of guanine nucleotides in the bacterial nucleotide pool, and that this contributes to the cytotoxicity of these antibiotics. [10] The incorporation of oxidized guanine nucleotides into DNA could be bactericidal since incomplete repair of closely spaced 8-oxo-2'-deoxyguanosine in the DNA can result in lethal double-strand breaks. [10]

Finally, a further "cell-membrane effect" also occurs with aminoglycosides; "functional integrity of the bacterial cell membrane" can be lost, later in time courses of aminoglycoside exposure and transport. [11]

Pharmacokinetics and pharmacodynamics

There is a significant variability in the relationship between the dose administered and the resultant plasma level in blood.[ citation needed ] 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, and allows a prolonged dosage interval.[ citation needed ] Depending on their concentration, they act as bacteriostatic or bactericidal agents. [12]

Indications

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. 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.[ citation needed ] The most frequent use of aminoglycosides is empiric therapy for serious infections such as sepsis, complicated intra-abdominal 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.[ citation needed ]

As noted, aminoglycosides are mostly ineffective against anaerobic bacteria, fungi, and viruses. [2] 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.[ citation needed ]

Nonsense suppression

The interference with mRNA proofreading has been exploited to treat genetic diseases that result from premature stop codons (leading to early termination of protein synthesis and truncated proteins). Aminoglycosides can cause the cell to overcome the stop codons, insert a random amino acid, and express a full-length protein. [13] 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 a 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. [14]

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. [15]

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. [16] 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 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. [17]

Aminoglycosides are in pregnancy category D, [18] that is, there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Adverse effects

Aminoglycosides can cause inner ear toxicity which can result in sensorineural hearing loss. [19] The incidence of inner ear toxicity varies from 7 to 90%, depending on the types of antibiotics used, susceptibility of the patient to such antibiotics, and the duration of antibiotic administration. [20]

Another serious and disabling side effect of aminoglycoside use is vestibular ototoxicity. [19] This leads to oscillopsia (gaze instability) and balance impairments that impact all aspects of an individual's antigravity function. This loss is permanent and can happen at any dose. [21] [22] [23] [24]

Frequent use of aminoglycosides could result in kidney damage (Acute kidney injury), that could lead to chronic kidney disease. [25]

Contraindication for specific diseases

Aminoglycosides can exacerbate weakness in patients with myasthenia gravis, and use is therefore avoided in these patients. [26]

Aminoglycosides are contraindicated in patients with mitochondrial diseases as they may result in impaired mtDNA translation, which can lead to irreversible hearing loss, tinnitus, cardiac toxicity, and renal toxicity. However, hearing loss and tinnitus have also been observed in some patients without mitochondrial diseases. [27]

Related Research Articles

<span class="mw-page-title-main">Streptomycin</span> Aminoglycoside antibiotic

Streptomycin is an antibiotic medication used to treat a number of bacterial infections, including tuberculosis, Mycobacterium avium complex, endocarditis, brucellosis, Burkholderia infection, plague, tularemia, and rat bite fever. For active tuberculosis it is often given together with isoniazid, rifampicin, and pyrazinamide. It is administered by injection into a vein or muscle.

<span class="mw-page-title-main">Neomycin</span> Type of antibiotic

Neomycin is an aminoglycoside antibiotic that displays bactericidal activity against Gram-negative aerobic bacilli and some anaerobic bacilli where resistance has not yet arisen. It is generally not effective against Gram-positive bacilli and anaerobic Gram-negative bacilli. Neomycin comes in oral and topical formulations, including creams, ointments, and eyedrops. Neomycin belongs to the aminoglycoside class of antibiotics that contain two or more amino sugars connected by glycosidic bonds.

<span class="mw-page-title-main">Gentamicin</span> Antibiotic medication

Gentamicin is an aminoglycoside antibiotic used to treat several types of bacterial infections. This may include bone infections, endocarditis, pelvic inflammatory disease, meningitis, pneumonia, urinary tract infections, and sepsis among others. It is not effective for gonorrhea or chlamydia infections. It can be given intravenously, by intramuscular injection, or topically. Topical formulations may be used in burns or for infections of the outside of the eye. It is often only used for two days until bacterial cultures determine what specific antibiotics the infection is sensitive to. The dose required should be monitored by blood testing.

<span class="mw-page-title-main">Aztreonam</span> Chemical compound

Aztreonam, sold under the brand name Azactam among others, is an antibiotic used primarily to treat infections caused by gram-negative bacteria such as Pseudomonas aeruginosa. This may include bone infections, endometritis, intra abdominal infections, pneumonia, urinary tract infections, and sepsis. It is given by intravenous or intramuscular injection or by inhalation.

<span class="mw-page-title-main">Neomycin/polymyxin B/bacitracin</span> Antibiotic medication

Neomycin/polymyxin B/bacitracin, also known as triple antibiotic ointment, is an antibiotic medication used to reduce the risk of infections following minor skin injuries. It contains the three antibiotics neomycin, polymyxin B, and bacitracin. It is for topical use.

<span class="mw-page-title-main">Paromomycin</span> Chemical compound

Paromomycin is an antimicrobial used to treat a number of parasitic infections including amebiasis, giardiasis, leishmaniasis, and tapeworm infection. It is a first-line treatment for amebiasis or giardiasis during pregnancy. Otherwise, it is generally a second line treatment option. It is taken by mouth, applied to the skin, or by injection into a muscle.

<span class="mw-page-title-main">Piperacillin</span> Antibiotic medication

Piperacillin is a broad-spectrum β-lactam antibiotic of the ureidopenicillin class. The chemical structure of piperacillin and other ureidopenicillins incorporates a polar side chain that enhances penetration into Gram-negative bacteria and reduces susceptibility to cleavage by Gram-negative beta lactamase enzymes. These properties confer activity against the important hospital pathogen Pseudomonas aeruginosa. Thus piperacillin is sometimes referred to as an "anti-pseudomonal penicillin".

<span class="mw-page-title-main">Kanamycin A</span> Antibiotic

Kanamycin A, often referred to simply as kanamycin, is an antibiotic used to treat severe bacterial infections and tuberculosis. It is not a first line treatment. It is used by mouth, injection into a vein, or injection into a muscle. Kanamycin is recommended for short-term use only, usually from 7 to 10 days. Since antibiotics only show activity against bacteria, it is ineffective in viral infections.

<span class="mw-page-title-main">Tobramycin</span> Chemical compound

Tobramycin is an aminoglycoside antibiotic derived from Streptomyces tenebrarius that is used to treat various types of bacterial infections, particularly Gram-negative infections. It is especially effective against species of Pseudomonas.

<span class="mw-page-title-main">Amikacin</span> Antibiotic medication

Amikacin is an antibiotic medication used for a number of bacterial infections. This includes joint infections, intra-abdominal infections, meningitis, pneumonia, sepsis, and urinary tract infections. It is also used for the treatment of multidrug-resistant tuberculosis. It is used by injection into a vein using an IV or into a muscle.

<span class="mw-page-title-main">Netilmicin</span> Chemical compound

Netilmicin (1-N-ethylsisomicin) is a semisynthetic aminoglycoside antibiotic, and a derivative of sisomicin, produced by Micromonospora inyoensis. Aminoglycoside 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.

<span class="mw-page-title-main">G418</span> Chemical compound

G418 (geneticin) is an aminoglycoside antibiotic similar in structure to gentamicin B1. It is produced by Micromonospora rhodorangea. G418 blocks polypeptide synthesis by inhibiting the elongation step in both prokaryotic and eukaryotic cells. Resistance to G418 is conferred by the neo gene from Tn5 encoding an aminoglycoside 3'-phosphotransferase, APT 3' II. G418 is an analog of neomycin sulfate, and has similar mechanism as neomycin. G418 is commonly used in laboratory research to select genetically engineered cells. In general for bacteria and algae concentrations of 5 μg/mL or less are used, for mammalian cells concentrations of approximately 400 μg/mL are used for selection and 200 μg/mL for maintenance. However, optimal concentration for resistant clones selection in mammalian cells depends on the cell line used as well as on the plasmid carrying the resistance gene, therefore antibiotic titration should be done to find the best condition for every experimental system. Titration should be done using antibiotic concentrations ranging from 100 μg/mL up to 1400 μg/mL. Resistant clones selection could require from 1 to up to 3 weeks.

<span class="mw-page-title-main">Kanamycin kinase</span>

Aminoglycoside-3'-phosphotransferase, also known as aminoglycoside kinase, is an enzyme that primarily catalyzes the addition of phosphate from ATP to the 3'-hydroxyl group of a 4,6-disubstituted aminoglycoside, such as kanamycin. However, APH(3') has also been found to phosphorylate at the 5'-hydroxyl group in 4,5-disubstituted aminoglycosides, which lack a 3'-hydroxyl group, and to diphosphorylate hydroxyl groups in aminoglycosides that have both 3'- and 5'-hydroxyl groups. Primarily positively charged at biological conditions, aminoglycosides bind to the negatively charged backbone of nucleic acids to disrupt protein synthesis, effectively inhibiting bacterial cell growth. APH(3') mediated phosphorylation of aminoglycosides effectively disrupts their mechanism of action, introducing a phosphate group that reduces their binding affinity due to steric hindrances and unfavorable electrostatic interactions. APH(3') is primarily found in certain species of gram-positive bacteria.

<span class="mw-page-title-main">Sisomicin</span> Chemical compound

Sisomicin, is an aminoglycoside antibiotic, isolated from the fermentation broth of Micromonospora inositola. It is a newer broad-spectrum aminoglycoside most structurally related to gentamicin.

<span class="mw-page-title-main">Dihydrostreptomycin</span> Chemical compound

Dihydrostreptomycin is a derivative of streptomycin that has a bactericidal properties. It is a semisynthetic aminoglycoside antibiotic used in the treatment of tuberculosis.

<span class="mw-page-title-main">Protein synthesis inhibitor</span> Inhibitors of translation

A protein synthesis inhibitor is a compound that stops or slows the growth or proliferation of cells by disrupting the processes that lead directly to the generation of new proteins.

<span class="mw-page-title-main">Arbekacin</span> Antibiotic

Arbekacin (INN) is a semisynthetic aminoglycoside antibiotic which was derived from kanamycin. It is primarily used for the treatment of infections caused by multi-resistant bacteria including methicillin-resistant Staphylococcus aureus (MRSA). Arbekacin was originally synthesized from dibekacin in 1973 by Hamao Umezawa and collaborators. 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.

<span class="mw-page-title-main">Pen-Strep</span> Antibiotic

Pen-Strep is a mixture of penicillin G and streptomycin that is widely used in mammalian cell culture media to prevent bacterial contamination. The solution contains 5,000 units of penicillin G which acts as the active base, and 5,000 micrograms of streptomycin (sulfate), formulated in 0.85% saline. In general, 50-100 units of Pen-Strep per milliliter of media is used to avoid contamination in cell culture. Thus, the retail product is generally 100 times more concentrated. It is recommended for use in cell culture applications at a concentration of 10 ml per liter. It is the most common antibiotic solution for the culture of mammalian cells and it does not have any adverse effects on the cells themselves. It was first introduced in 1955 in cell culture.

<span class="mw-page-title-main">Ototoxic medication</span>

Ototoxicity is defined as the toxic effect on the functioning of the inner ear, which may lead to temporary or permanent hearing loss (cochleotoxic) and balancing problems (vestibulotoxic). Drugs or pharmaceutical agents inducing ototoxicity are regarded as ototoxic medications.

References

  1. ↑ E.g., see www.merriam-webster.com/medical/aminoglycoside: "any of a group of antibiotics (as streptomycin and neomycin) that inhibit bacterial protein synthesis and are active especially against gram-negative bacteria".
  2. 1 2 3 4 5 6 7 Mingeot-Leclercq MP, Glupczynski Y, Tulkens PM (1999). "Aminoglycosides: activity and resistance". Antimicrob. Agents Chemother. 43 (4): 727–37. doi:10.1128/AAC.43.4.727. PMC   89199 . PMID   10103173.
  3. 1 2 3 ME Levison, MD, 2012, Aminoglycosides, The Merck Manual , accessed 22 February 2014.
  4. ↑ Kroppenstedt RM, Mayilraj S, Wink JM (June 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): 328–39. Bibcode:2005SyApM..28..328K. doi:10.1016/j.syapm.2004.12.011. PMID   15997706.
  5. ↑ Paul M. Dewick (2009). Medicinal Natural Products: A Biosynthetic Approach (3rd ed.). Wiley. ISBN   978-0-470-74167-2.
  6. ↑ Hammes, Walter P.; Neuhaus, Francis C. (1974). "On the Mechanism of Action of Vancomycin: Inhibition of Peptidoglycan Synthesis in Gaffkya homari". Antimicrobial Agents and Chemotherapy. 6 (6): 722–8. doi:10.1128/AAC.6.6.722. PMC   444726 . PMID   4451345.
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  9. ↑ Aguirre Rivera, Javier (2021). "Real-time measurements of aminoglycoside effects on protein synthesis in live cells". Proceedings of the National Academy of Sciences. 118 (9): e2013315118. Bibcode:2021PNAS..11813315A. doi: 10.1073/pnas.2013315118 . PMC   7936356 . PMID   33619089.
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  11. ↑ As Boothe notes, "high concentrations of aminoglycosides may cause nonspecific membrane toxicity, even to the point of bacterial cell lysis", though the physiologic relevance of these concentrations to specific clinical situations is unclear. DVM Boothe, DVM, PhD, 2012, Aminoglycosides (Aminocyclitols), The Merck Veterinary Manual "Aminoglycosides: Antibacterial Agents: Merck Veterinary Manual". Archived from the original on 2014-03-01. Retrieved 2014-02-22., accessed 22 February 2014.
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  17. ↑ Durante-Mangoni, Emanuele; Grammatikos, Alexandros; Utili, Riccardo; Falagas, Matthew E. (2009). "Do we still need the aminoglycosides?". International Journal of Antimicrobial Agents. 33 (3): 201–5. doi:10.1016/j.ijantimicag.2008.09.001. PMID   18976888.
  18. ↑ Merck Manual: Bacteria and Antibacterial Drugs: Aminoglycosides Last full review/revision July 2009 by Matthew E. Levison, MD
  19. 1 2 Selimoglu, Erol (2007). "Aminoglycoside-induced ototoxicity". Current Pharmaceutical Design. 13 (1): 119–126. doi:10.2174/138161207779313731. PMID   17266591.
  20. ↑ L, Peterson; C, Rogers (18 February 2015). "Aminoglycoside-induced hearing deficits – a review of cochlear ototoxicity". South African Family Practice. 57 (2): 77–82. doi: 10.1080/20786190.2014.1002220 .
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  27. ↑ referenced in Bindu, LH; Reddy, PP (2008). "Genetics of aminoglycoside-induced and prelingual non-syndromic mitochondrial hearing impairment: a review". Int J Audiol. 47 (11): 702–7. doi:10.1080/14992020802215862. PMID   19031229. S2CID   25797666. See Also Fischel-Ghodsian, N (1999). "Genetic factors in aminoglycoside toxicity". Ann N Y Acad Sci. 884 (1): 99–109. Bibcode:1999NYASA.884...99F. doi:10.1111/j.1749-6632.1999.tb08639.x. PMID   10842587. S2CID   10280462.
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