-1-Lecture 13: AminoglycosidesDolly Mehta, Ph.D.Knowledge Objectives1. Know the basic processes of bacterial protein synthesis.2. Know the mechanism of antimicrobial activity for aminoglycosides.4. Know the most common adverse effects.5. Know the mechanisms of bacterial resistance.6. Know the most common applications of these antibiotics for the treatment ofdisease. Which drugs are broad spectrum, and which have specific or unique uses.Drug ListAminoglycosides neomycingentamicinstreptomycinamikacintobramycinkanamycin1Drugs inhibiting Protein SynthesisAminoglycosides and MacrolidesTeteracycline and Chloramphenicolyp1Protein Synthesizing machineryRibosomebacteria has 50S and 30 S subunit which forms 70 S polysome that slides on mRNAhas A, P and E sites for binding with tRNAmRNAtRNAforms template for protein synthesistranscribed from DNAattaches to 30s ribosomesbrings amino acidsattaches to A, P and E sites of ribosomes2Overview:3EPA42TransferaseEPA5EPA67Eukaryotes : 60S and 40 S subunitDifference in ribosomal units is the basis of Why antibiotic drugs do not inhibit mammalian protein synthesis?? selectivity of antimicrobial drugs against bacteria83AminoglycosidesGentamicinTobramicinAmikacinNetilmicinKanamycincomposed of amino-sugars water-soluble (hydrophillic)highly polarizedKanamycinStreptomycin9Kanamycin2-deoxystreptamineKanamycin A,BTobramycinamikacinypstreptidineStreptomycin10Pil iPGAGEnergy-Dependent Phase 1Aminoglycosides EntryPeriplasmic spacePBPPBPrate limitingrequires (-) inner potentialgyp(EDP1)11II. Mechanism of Action:a) binds to A site of 30s of ribosome subuniti i t f ith th f ti f th i iti ti liii. Premature termination of mRNA translationi. interfere with the formation of the initiation complexii. induce misreading of the mRNA templateiv. cause polysomes to break up into monosomes124b) Create fissure inducing bacterial damage (contrast from Tetra or Chloram) further enhancing AG uptake (EDP2 phase)13pHCa2+/Mg2+Entry to the inner membrane requires Transmembrane electrical potentialEffectiveness(Abcess, hyperosmolar gHyperosmolarityAnearobic conditionsypacidic urine)14Bacterial killing Æ concentration dependentPost-antibiotic effect persists after the serum conc < minimum inhibitory concentration (MIC)Once daily dose of aminoglycosides is therefore efficacious15VIII. Mechanisms of Resistance Intracellular penetrationModification of the ribosomal binding siteLow affinity of drug for bacterial ribosomesGroup tftransferases acetylation, phosphorylation, adenylation of OH or NH2 gr Drug inactivationMetabolites can also compete with AG165Cross-resistance by other aminoglycosidesi.e. gentamicin Ætobramicin, amikamicin, kanamycin and netilmycin. No effect on Steptomicin17AAC: acetylases; ANT: adenylase; APH, phosphorylase1819Enzyme Genes Selected AminoglycosideSubstratesCommentsAcetylationAAC(3)-I aac(3)-Iaaac(3)-IbGmAAC(3)-II aac(3)-Iiaaac(3)-Iibaac(3)-IicGm, TobAAC(3)-III aac(3)-IIIaaac(3)-IIIb(3)IIIGm, Tob, Km, Neo, PrmCommonly found in Pseudomonas spp.Rl iaac(3)-IIIcRarely seen in Enterobacteriaceae AAC(3)-IV aac(3)-Iva Gm, Tob Commonly found in Salmonella spp.AAC(3)-VI aac(3)-Via Gm Resistance to Tob and Km not conferred; however a low-level of enzymatic activity has been detected.Rare among Enterobacteriaceae206AAC(6’)-I aac(6’)-Iaaac(6’)-Ibaac(6’)-Icaac(6’)-Idaac(6’)-Ieaac(6’)-Ifaac(6’)-Igaac(6’)-Ihaac(6’)-IiTob, AmkAAC(6’)-IIaac(6’)-IiaGm TobObserved only inPAAC(6 )IIaac(6 )Iiaaac(6’)-IibGm, TobObserved only in P. aeruginosaAAC(6’)-APH(2”)aac(6’)-aph(2”) Gm, Tob, Amk Bifunctionalenzyme thought to be restricted to gram positive bacteria. (staphylococci and enterococci)AAC(2’-I) aac(2’)-Ia Gm, Tob21AdenylylationANT(2”)-I ant(2”)-Iaant(2”)-Ibant(2”)-IcGm, Tob, Km Widespread among all gram-negative bacteriaANT(3”)Iant(3”)IaSm SpcmANT(3 )-Iant(3 )-IaSm, SpcmANT(4’)-I ant(4’)-Ia Tob, AmkANT(4’)-II ant(4’)-Iia Tob, AmkANT(6)-I ant(6)-Ia Sm Found in gram-positive organisms22PhosphorylationAPH(2”)-I aph(2”)-Ia Gm, Tob, AmkAPH(3’)-I aph(3’)-Iaaph(3’)-Ibaph(3’)-IcKm, Neo, PrmAPH(3’)-II aph(3’)-Iia Km, Neo, Prm, GmBAPH(3’)-III aph(3’)-IIIa Km, Neo, Prm, Amk, GmBCommonly found in S. aureus and E. faecalisAPH(3’)-IV aph(3’)-Iva Km, Neo, PrmAPH(3’)-V aph(3’)-Vaaph(3’)-Vbaph(3’)-Vc23APH(3’)-VI aph(3’)-Viaaph(3’)-VibKm, Neo, Prm, Amk, GmBPrimarily isolated from Acinetobacter spp.APH(3’)-VII aph(3’)VIIa Km, Neo Cloned from Campylobacter jejuniAPH(3”)-I aph(3”)-Iaaph(3”)-IbSm Cloned from Streptomyces griseusAPH(6)-I aph(6)-Iaaph(6)-Ibaph(6)-Icaph(6)-IdSm Cloned from Streptomycesspp.247Oral or rectal administration: <1% of dose is abosorbedRapidly absorbed from I.M; peak conc. in plasma occur after 30-90 min period 4-12 ug/ml following 15-2 mg/kg doseVI. Absorption1.5-2 mg/kg dose 25μg/ml0102030q24hq8hthresholdhours4812 16 202400Plasma concentrations after IV injection of 5.1 mg/kg to a hypothetical patient either as a single (q24h) or as three divided doses (q8h)26DistributionDo not cross BBB and do not achieve high distribution in body fluids.Can cross placenta27Excreted entirely via the kidneys and urine conc of 50-200 ug/ml are acheived.Clearance faster from plasma as compared to tissuesExcretionClearance similar in adults and children older than 6 months; half life is prolonged in The dosage must be adjusted for renal function. Should not be administered to patients in renal failure288Spectrum:Aerobic Gram (-) bacilli.Kanamycin and Streptomycin: limited spectrumShould not be used for infections caused by Serratia or P.aeruginosaIst-line drug for pseudomonas. Ist -line drug for pseudomonas.May be given with penicillin in infections caused by streptococci, Listeria sp.Anaerobic or facultative anaerobic bacteria are resistant 29Side EffectsOtotoxicity (vestibular and auditory dysfunction)Largely irreversible30123Cochlea, normally lined with hair cells that are destroyed by high concentrations ofaminoglycosides. Aminoglycosides damage hair cells, especially in turn No. 1 and part of turn No. 2. Hairs are shed by the damaged cells to give loss of high-frequency response first (associated with turn No. 1) and low-frequency loss later (associated with turn to. 3). 31amikacin, kanamycin, neomycincochlear damage lfhihf tloss of high frequency tones 329streptomycin and gentamicin vestibular damage loss of low frequency tones Loop diuretics (furosemide and ethacrynic acid)
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