An Illustrated Review About Aminoglycosides · An Illustrated Review About Aminoglycosides ... rapid concentration-dependent bactericidal effect, ... and understand quickly during

Article ID: WMC002744 2046-1690

An Illustrated Review About AminoglycosidesCorresponding Author:Dr. Aisyah S Abdul Rahim,Senior Lecturer, Discipline of Pharmaceutical Chemistry School of Pharmaceutical Sciences Universiti SainsMalaysia, Universiti Sains Malaysia, Minden, Pulau Pinang - Malaysia, 11800 - Malaysia

Submitting Author:Mr. Kwek C Hau,Undergraduate, School of Pharmaceutical Sciences Universiti Sains Malaysia, 11800 - Malaysia

Article ID: WMC002744

Article Type: Review articles

Submitted on:19-Dec-2011, 01:24:31 PM GMT Published on: 19-Dec-2011, 03:31:23 PM GMT

Article URL: http://www.webmedcentral.com/article_view/2744

Subject Categories:PHARMACEUTICAL SCIENCES

Keywords:Aminoglycoside Streptomycin Neomycin Kanamycin Gentamycin

How to cite the article:Abdul Rahim A S, Muhamad Sayuti M , Hau K C, Ee D C, Wan Zaki W , Raskitar N ,Kanasin R . An Illustrated Review About Aminoglycosides . WebmedCentral PHARMACEUTICAL SCIENCES2011;2(12):WMC002744

Copyright: This is an open-access article distributed under the terms of the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the originalauthor and source are credited.

WebmedCentral > Review articles Page 1 of 14

http://www.webmedcentral.com/article_view/2744

http://creativecommons.org/licenses/by/3.0/

http://creativecommons.org/licenses/by/3.0/

WMC002744 Downloaded from http://www.webmedcentral.com on 19-Dec-2011, 03:31:23 PM

An Illustrated Review About AminoglycosidesAuthor(s): Abdul Rahim A S, Muhamad Sayuti M , Hau K C, Ee D C, Wan Zaki W , Raskitar N , Kanasin R

Abstract

Aminoglycoside is a potent antibiotic that stops theprotein synthesis continuation by binding to theribosomal decoding site. They are used to treatinfection caused by the aerobic, gram-negative andcertain gram-positive organisms. The most commonlyused aminoglycoside is Gentamicin. Generally, singledaily dosing of aminoglycosides is appeared to besafer, cost effective and efficacious. Prolonged use ofthe drugs will lead to side effects such as ototoxicityand nephrotox ic i ty . Res is tance towardsaminoglycoside is possible but it rarely happens. Thestructures activity relationship (SAR) of someaminoglycoside antibiotics is further reviewed in thispaper.

Introduction

Aminoglycoside has been found 50 years ago andbecause of their excellent attainment, it was still usedas a drug of choice to give various functions includingrapid concentration-dependent bactericidal effect,synergism with beta-lactam antibiotics, clinicaleffectiveness, a low rate of true resistance and it isalso low cost [1].The first aminoglycoside found, streptomycin, wasisolated from Streptomyces griseus in the year 1943[2]. On the other hand, aminoglycosides that wasusually given topically, neomycin,was isolated fromStreptomyces fradiae, had better activity thanstreptomycin against aerobic gram-negative bacilli [2].Gentamicin, was isolated from Micromonospora in theyear 1963, was a breakthrough in the treatment ofgram-negative bacillary infections, including thosecaused by Pseudomonas aeruginosa [2].The aminoglycosides remain drugs of choice intreating many diseases including septicaemia, seriousinfections due to Gram negative bacilli, and bacterialendocarditis [1]. Streptomycin, the earlieastaminoglycosides found, is used to treat infections liketberculous meningitis, plague, brucellosis, andtularaemia. Tobramycin is used to treat seriousbacterial infections caused by susceptible strains inlower respiratory tract which is an infection caused bybacteria P. Aerugionosa, Enterobater sp, E. Coli,Klebsiella sp, and S. Aureus[3] .Amikacin SulphateInjection, USP is indicated in the short-term treatment

of serious infections due to susceptible strains ofgram-negative bacteria, including Pseudomonas sp, E.Coli, species of indole negative and indole positiveProteus, Providencia sp, Klebsiella-Enterobacter-Serratia sp, and Actinobacter sp. [4]

Classification and SAR ofAminoglycoside Antibiotics

Natural aminoglycoside antibiotics share a non-sugar2-deoxystreptamine scaffold connected to aminosugar substituents at the 4-, 5- and 6-positions. Thetwo most important classes of aminoglycosideantibiotics are the 4, 5- and 4, 6-disubstituted2-deoxystreptamine derivatives. [5] The 4,5-disubstituted 2-deoxystreptamine compoundsinclude neomycin B whereas the 4,6-disubstituted 2deoxystreptamine derivatives include gentamycin,kanamycin and streptomycin. Aminoglycosideantibiotics of these three groups, 4, 5- and 4,6-disubstituted 2-DOS derivatives and apramycin,share in common a target site at the decoding center(A-site) of bacterial 16S ribosomal RNA (rRNA).2-deoxys t reptamine scaf fo ld is the keypharmacophore required for the precise anchoring ofthe drugs at the RNA target. [6]1. StreptomycinStreptomycin is the first aminoglycoside antibiotic tobe discovered and was the first antibiotic to be used intreatment of tuberculosis. It was discovered in 1943, inthe laboratory of Selman Waksman at RutgersUniversity. Streptomycin is derived from the bacteriumStreptomyces griseus.It inhibits bacterial growth byinhibiting protein synthesis. Specifically, it binds to the16S rRNA of the bacterial ribosome, interfering withthe binding of formyl-methionyl-tRNA to the 30Ssubunit.It is chemically stable and rapidly bactericidal,with a broad spectrum of inhibitory ctivity (apart fromanaerobic bacteria).[7] Streptose, the central moiety, isa C-3-formyl derivative of 5-deoxy-Llyxose.[8] Twomajor precursors of the streptidine portion of themolecule have nowbeen defined, n-arginine andn-glucose (1, 2). [9]2.NeomycinNeomycin, an aminoglycoside antibiotic, discoveredon 1949 in the lab of Selman Waksman.It hasexcellent activity against gram-negative bacteria, andhas partial activity against gram-positive bacteria. It isproduced naturally by the bacterium Streptomyces



fradiae. Most potent aminoglycoside translationinhibitors [10].3.KanamycinKanamycin is made up of 3 rings. Ring II is sugargroup,while ring I and III are non-sugar group.Kanamycin B is a more potent antibiotic than eitherkanamycins A or C. The presence of a diaminohexose, therefore, results in a compound that is abetter inhibitor of protein synthesis than one containingonly one amino group.Therefore, when only one aminogroup is present, an antibiotic that contains a 6-aminosubstituent is more active than one containing a2-amino substituent.antibiotic activity can be related tothe number and location of amino groups in thehexose moiety glycosidically linked to the 4-position ofdeoxystreptamine as follows (in decreasing order ofpotency): 2', 6'-diamino > 6'-amino > 2'-amino > noamino4.GentamicinThere have 3 types of gentamicin in this class ofaminoglycosides such as Gentamicin C1, GentamicinC2 and Gentamicin C1a. Gentamicin C1 exists whenboth R1 and R2 are CH3. Gentami cin C2 exists whenR1 is CH3 and R2 is H. Gentamicin C1a exists whenboth R1 and R2 are H. The structure of gentamicin isconsistent with the aminoglycoside structural activityrelationship(SAR), except few minor changes.Gentamicin C1a binds in the major groove of the RNA.

Discussion

Illustration is a very useful method in explaining aparticular matter with the use of only limited words.Images also produce a longer memory in our mind andit leads to the reason why we prefer to do an illustratedreview on this topic.In the beginning of our review, an illustration is used toexplain the general uses of aminoglycosides and itshows exactly where the drugs should be applied to.Besides, several illustrations and structures have beenused to illustrate the mechanism of action ofaminoglycosides on the ribosomal subunit. This is toprovide a more vivid idea on how a drug attaches tothe specific part of the ribosomes and render theproduction of non-functional protein which eventuallybecomes detrimental to the bacteria. We also resort tothe presentation of information in table form. It enablesus to compare and contrast the spectrum of activity,clinical indication, pharmacokinetic and side effects ofdifferent types of aminoglycosides. By presenting allthe information in a table, similarities and differencesamong them are more obvious as compared toexplaining them in separate way. For examples, it is

obviously depicted in the table that aminoglycosidesare effective against both gram positive and gramnegative bacteria.Our visual memory is much more powerful than ouraudio memory. Converting a whole page of notes intopictures or illustrations ensures that we understand theinformation, we are summarising it and converting itinto a picture. It will be so much easier to recall thispicture from memory during an exam than to recallevery word on a page of text. Using coloured picturesor illustrations to focus on main part of chemicalstructures stimulates our mind to remember thestructure very well and its specifications. It acts as aninstant guide for pharmacy students to read thoroughlyand understand quickly during last minute revision orfinal preparations to avoid wasting time reading notesin a long essay form. A structure with illustration used in explaining thestructure relationship activity of aminoglycoside notonly can facilitate the conceptualization anddissemination of information through it, but alsomotivate students to read it. With the important pointsfitted into each part of structure, it can help thestudents to interpret the structure more easily. Theymust be related to the text content with the structure ofaminoglycoside because it is the nature of illustrations.As a result, they can know clearly about the function ofeach part of structure rather than when we separatethe point with the structure. This is because it willmake them confused and it is more difficult to relatethe text content with the structure. It is a tedious taskfor them to find out the points that correspond for eachpart of drug structure. This is correlated with researchdone by Russell N. Carney which stated thatillustration improve students’ learning from textbecause they make the text more concentrated,concrete, coherent, comprehensible, correspondentand codable [19] . An illustration form of drug structurecan have representation and interpretation function.The more difficult the text is to be understood, themore the illustration helps.For an illustrated article, a striking colour also plays amajor role in helping the reader to recall facts andinformation. As compared to the black and whitesentences or diagrams, the coloured one will make iteasier for someone to focus on what they have tomemorize and vice versa. Normally we use a strikingcolour such as red and yellow to emphasize thekeywords or main points and we are likely to retain theinformation and remember them better. Colour tendsto be processed by the right side of the brain and byintroducing the colour into the information, it willstimulates more of your brain than if you just using onecolour. By using colour, it makes the article far more



interesting to look at, therefore much more engagingto the emotions and stimulates senses at the sametime. Coloured diagrams, tables or explanations areimportant especially if you are doing a tedious ordifficult topic.In our opinions, we think that aminoglycosides arevery useful in fighting a wide range of disease-causingbacteria. In reality, they have been to treat urinary tractinfection caused by E. coli and other bacteria.Furthermore, Streptomycin is being used as a first lineagent in treating Tuberculosis disease which is causedby the Mycobacterium Tuberculosis. Most of them aregiven as intramuscular and intravenous injections. Theonly drug that can be taken orally in this class is theNeomycin due to its high toxicity if given parenterally. All members of aminoglycoside family of drugs can beototoxic and nephrotoxic. We think that the side effectsand toxicity should not be a reason to state that a drug“should not be used”. It is a matter that whether thedecision making on based on age, renal function andoverall condition of the patient is done correctly.Obviously, gentamycin should not be used if a patienthas a decreased renal function because it will lead todrug accumulation and increased toxicity.

Conclusion

The most important classes of aminoglycosidesantibiotics are the 4, 5- and 4, 6-disubstituted2-deoxystreptamine derivat ives. Dif ferentaminoglycosides antibiotics possess differentstructures especially on the rings and the functionalgroup. The differences in functional groups could bethe contributing reasons to the variety of actions ofdifferent aminoglycosides antibiotics.Two mechanisms of act ion involv ing theaminoglycosides antibiotic are by interfering with thetranslation by causing a misreading of the codonsalong the mRNA and by interfering with thetranslocation of tRNA from A-Site to P-site.Aminoglycosides have concentration-dependenetkilling action active against the gram-negative bacilli.But, neomycin, kanamycin and gentamycin activeagainst both gram positive and gram negative bacteria.Gentamycin is the most commonly usedaminoglycosides. Aminoglycosides are not advised tobe given orally because they are poorly absorbed inGIT. It is normally given via intravenous orintramuscular injection.Aminoglycosides are very effective in treating patientwith the gram negative bacteria. But, it can causenephrotoxicity and ototoxicity and only be given whenin the cases of serious gram-negative systemic

infection. If it is given to the patient with renal failure,dose monitoring must be conducted to avoid seriousside effects such as toxicity of aminoglycosides.

References

1.Begg EJ, Barclay ML, (1995). Aminoglycosides-50years on. [Online], vol.39, no.6, pp.597, Abstract only.Available: PubMed Central. [Accessed 11 November2011] .2.Gonzalez LS, Spencer JP, (1998). Aminoglycosides:A Practical Review. [Online] Pennsylvania: TheAmerican Academy of Family Physicians. Available:http://www.aafp.org/afp/981115ap/gonzalez.html[Accessed 11 November 2011].3.Drugs.com, (2005). Tobramycin. [online] Available at:http://www.drugs.com/pro/tobramycin.html [Accesseddate: 11 November 2011]4.Drugs.com, (2004). Amikacin. [online] Available at:http://www.drugs.com/pro/amikacin.html[Accesseddate: 11 November 2011]5.T.Hermann (2007). Aminoglycoside antibiotics: olddrugs and new therapeutic approaches. Cellular andMolecular Life Sciences.Edtion 64, pp.1841 – 18526.Busscher, G. F., Rutjes, F. P. and van Delft, F. L.(2005). 2-Deoxystreptamine: central scaffold ofaminoglycoside antibiotics.Chem. Rev. 105, pp.775 –791.7.Antibiotics used in the treatment of infectiousd i s e a s e . ( 2 0 1 1 ) . [ O N L I N E ] A v a i l a b l eat:http://textbookofbacteriology.net/themicrobialworld/antimicrobial.html [Accessed 07 November 2011]8.Joseph Bruton, Will iam H.Horner.(1966).Biosynthesis of Streptomycin (III. Origin of The carbonAtoms of Streptose). The Journal of BiologicalChemistry. [ONLINE].Vol.24, pp. 3142-3146. Availablefrom: http://www.jbc.org [Accessed 08 November2011].9.William H.Horner. (July 1964). Biosynthesis ofStreptomycin (II.Myo-inositol, A Precursor of TheStreptidine Moiety). The Journal of BiologicalChemistry. [ONLINE].Vol 239, 2256-2258. Availablefrom : http://www.jbc.org. [Accessed 08 November2011].10.Fang Zhao, Qiang Zhao, Kenneth F. Blount, QingHan, Yitzhak Tor, and Thomas Hermann. (2005).Molecular Recognition of RNA by Neomycin and aRestricted Neomycin Derivative. StructuralBiochemistry. [ONLINE]. Vol. 44, pp.5329 –5334.A v a i l a b l e f r o m :http://onlinelibrary.wiley.com/doi/10.1002/anie.200500903/full11.Satoko Yoshizawa, Dominique Fourmy et al (1998)



Structural origins of gentamicin antibiotic action. TheEMBO Journal ,Vol 17, No.22, pp.6437-6448.12.Mehta A., (2010). Mechanism of Action ofAminoglycosides, PharmaXChange.info. [online]A v a i l a b l eat:http://pharmaxchange.info/press/2011/05/mechanism-of-action-of-aminoglycosides/[Accessed: 11November 2011]13.World Health Organization Geneva, (2001). WHOmodel prescribing information: drugs used in bacterialinfection, pp.177.14.Mingeot-Leclercq MP, Glupczynski Y, and TulkensPM. (1999) Aminoglycosides: Activity and Resistance.Antimicrobial Agents and Chemotherapy. Vol. 43,pp.727-37.15.Nikaido, H. and Vaara, M. (1985) Molecular basisof bacterial outer membrane permeability. Microbiol.Rev. 49, pp.1–32.16.Hancock, R.E.W., Farmer, S.W., Li, Z. and Poole,K. (1991) Interaction of aminoglycosides with the outermembranes and purified lipopolysaccharide andOmpF porin of Escherichia coli. Antimicrob. AgentsChemother. Vol.35, pp.1309–1314.17.Davies J., Wright G. D. (1997) Bacterial resistanceto aminoglycoside antibiotics. Trends Microbiol. Vol.5,pp.234–240.18.Kucers A, Crowe S, Grayson ML, and Hoy J, eds.(1997) The Use of Antibiotics: A Clinical Review ofAntibacterial, Antifungal, and Antiviral Drugs, 5thedition, Oxford: Butterworth Heinemann, pp.452-457.19.Russell N. Carney, Joel R. Levin (2002) PictorialIllustrations Still Improve Students’Learning From Text,Educational Psychology Review, Vol. 14, No. 1.



Illustrations

Illustration 1

Aminoglycoside uses

Illustration 2

Streptomycin



Illustration 3

Neomycin

Illustration 4

Gentamicin



Illustration 5

Kanamycin

Illustration 6

Mechanism of action: a) Interfering with translation by causing a misreading of the codonsalong the mRNA (Step I)



Illustration 7

Step 2

Illustration 8

Step 3



Illustration 9

b) Interfering with the translocation of tRNA from the A-Site to the P-Site (Step 1)

Illustration 10

Step 2



Illustration 11

Step 3

Illustration 12

Comparisons between Streptomycin, Neomycin, Kanamycin and Gentamycin



Illustration 13

Mechanism of Resistance: a) Reduced uptake or decreased cell permeability

Illustration 14

b) Production of aminoglycoside modifying enzymes



Illustration 15

c) Alterations at the ribosomal binding sites



DisclaimerThis article has been downloaded from WebmedCentral. With our unique author driven post publication peerreview, contents posted on this web portal do not undergo any prepublication peer or editorial review. It iscompletely the responsibility of the authors to ensure not only scientific and ethical standards of the manuscriptbut also its grammatical accuracy. Authors must ensure that they obtain all the necessary permissions beforesubmitting any information that requires obtaining a consent or approval from a third party. Authors should alsoensure not to submit any information which they do not have the copyright of or of which they have transferredthe copyrights to a third party.

Contents on WebmedCentral are purely for biomedical researchers and scientists. They are not meant to cater tothe needs of an individual patient. The web portal or any content(s) therein is neither designed to support, norreplace, the relationship that exists between a patient/site visitor and his/her physician. Your use of theWebmedCentral site and its contents is entirely at your own risk. We do not take any responsibility for any harmthat you may suffer or inflict on a third person by following the contents of this website.


Documents

An Illustrated Review About Aminoglycosides · An Illustrated Review About Aminoglycosides ... rapid concentration-dependent bactericidal effect, ... and understand quickly during