As's/2 Dr.Noor H. Aldabagh ews vs l C\ X35 Aminoglycosides Aminoglycosides are so named because their structures consist of amino sugars linked glycosidically. All have at least one aminohexose, and some a have a pentose lacking an amino group (e.g; streptomycin, neomycin, and paromomycin). Additionally, each of the clinically useful amin glycosides contains a high! kanamycin, neomyein, gentamycin, and tobramycin, itis zoxystreptamine] and in streptomycin, it is ‘streptadine The a —— are thus strongly basic compounds that exist as polycations at physi _pH. ‘Their inorganic acid salts are very soluble in water, All are available as — sn asin wees sulfates. Solutions of the aminoglycoside salts are stable to autoclaving. eae fae cee ath The high v water ee of. the aminoglycosides no doubt contributes to They tend to concentrate in the le are excreted by glomerular filtration. Aminoglycosides apparently not metabolized in vivo. = 1 hese. ate sgetutal prada sola tn the actinomycetes _at particularly, from genus Strepromyees. Al_uminoglycoside antibiotics are absorbed very poorly (less than 1% under normal circumstances) following oral administration, and some of Lstone — — STEP. Dear ar er veener raat them (kanamycin, neomycin, and paromomycin) are administered by that Asse ies Ss eke Maal Pe ded aL route for the treatment of gastrointestinal infections. Because of their potent broad-spectrum antimicrobial activity, they are also used for the treatment of systemic infections. Their undesirable side effects, particularly CTOIONTETTS wanderfephrotoxicity;) ‘eiiyyhave restricted their systemic use to serious infections or infectior iS paoienael by bacterial strains resistant to other age When sn administered for systemic infections, aminoglycosides must be given ts. parenterally, usually by intramuscular injection. : 1ARNO ICOM - Mechanism of Action: Aminoglycosides act directly on the bacterial ribosome to inhibit the initiation of protein synthesis and to interfere with the fidelity of translation of the genetic message. They hind to the 30S ribosomal subunit to form a ee eee complex that cannot initiate proper amino acid polymerization. The binding of streptomycin and other aminoglycosides to ribosomes also causes nf sireptomyeineandsclhey, oglycosides to misreading mutations of the genetic code, apparently resulting from failure of specific aminoacyl RNAs to recognize the proper codons on mRNA and | hence incorporation of improper amino acids into the peptide chain. Spectrum of Activity: Although the aminoglycosides are classified as broad-spectrum antibiotic: their r greatest usefulness lies in the treatment of serious systemic infections caused by serobic)Gram fregative bacilli. The choice of agent is generally between kanamycin, gentamicin, tobramycin, netilmicin, and amtk Aerobic Gram-negative and Gram-positive cocei (with the exception of staphy lococci) tend to be less sensitive: thus, the f-! Jactams and other antibiotics tend to be preferred for the treatment of infections caused by these organisms. Anaerobic bacteria are invariably resistant_to the aminoglycosides. the most eflective of the group for the chemotherapy of brucellosis, tularemia, and Yersinia __infections. “Paromomycin") is used primarily in the chemotherapy of amebic dysenery. Under certain circumstances, aminoglycoside and ica when the two are administered jointly. (Damage to the cell wall caused by the 1e_fe-lactams antibiotic is believed to increase penetration of the aminoglycoside into the bacterial cell). For example, carbenicillin and We 65 nega HYOO Aminoglycosicie Dr.Noor H. Aldabagh gentamicin are synergistic against gentamicin sensitive strains of P. en aa ks aeruginosa, and several other species of Gram. antibiotic types should are chemically incompatible. yy ‘vm abosat. %, pean We ae cKoSat § ' is —— Te § Poy egative bacilli, The two ¢ combined in the same solution because they Structure-Activity Relationships: It is convenient to discuss sequentially aminoglycosides SARs in terms of substituents in rings I, II, and III Ring (1) is crucially important for characteristic broad-spectrum ‘ima antibacterial activity, and it is th ry target for bacterial inactivating Amino functions at 6’ : —E—E—EO—EE——EE——E——E Ore kanamycin}B |(6'-amino. 0) is more active than kanamycin fA \6'- “amino, 2'-hydraxyl), w) more active than kanamycin SARS AA hydroxyl, 2'-amino) Methylation at either the 6'-carbon or the 6amino positions does not lower 6. appreciably antibacterial activity and confers resistance to enzymatic Se aN eee ee acetylation of the 6'-amino group. Removal of the 3'-hydroxyl or the 4'- A ne mae hydroxy! group or both in the Kinamycin (e.g., 3',4'- dideoxykanamycin B ; Moteion Fp, am jueAminogiycoside Dr.Noor H, eee nee ON RASC uc Kanosamine Voss rexve SS A Give Than © o™ Kanamycin A: Ry - NHz: Ry = OH move effe Oe Kanamycin 8: Ry - NH Ag = NH may? FEC Ie mega fo ¥iC Kanamycin 0: A, ~ OH: A, - NH; Chromatography showed that S. kanamyceticus elaborates three closely related struc amycins A, B, and C. Commi mercially available s ananycine a differ ont in the sugar moieties attached to the glycosidic oxygen on the 4 position of the central deoxystreptamine The chemical relationships among the kanamycins, the neomycins, and the sauclicdiaias oe oe paromomycins were a and showed that the kanamycins do nothave — - ARES COE ON Perhaps this structural differences is related to the Tower toxicity observed namycins, while it is increase the toxicity of the neomyc with k paromomycins, Ring (), Few modifications of ring II (deoxystreptamine) functional groups are possible without appreciable loss of activity in_most_of the aminoglycosides. The 1-amino group of kanamycin /A)can be acylated (e.g. amikacin), however, with activity largely retained, , 5 ~ == Ring (111), functional groups appear to be somewhat less sensetive to structural changes than those of either ring I or_ring II. Although the ural changes thanstose/on eben ane Morsring deoxygentamicins are significantly less active than their 2"-hydroxy! counterparts, the 2’ "amino derivatives (seldomycins) are highly active. The £ dutwrive of Fousranga~Aminoglycoside Dr.Noor H. Aldabagh rien 3"-amino group of gentamicin may be primary or secondary with high eee ee ee antibacterial potency. Furthermore, the 4"-hydroxyl group may he axial or = — ma rees equatorial with little change in potency. + Ruf NHR, ae, KN : Ho : = o-7 ay = 1 1 on alt S_< én, Gentamicin C,: R,=R,=CH, Gentamicin Gy: R\=CH, A.-H Gentamicin Cy_: Ry -R.-H Gentamicin is effective in the treatment of a variety of skin infections hich a topical cream or ointment may be used. It is recommended that w topical gentamicin be reserved for_use in the treatment of bugp complicated by pseudomonemia. An injectable solution containing 40 mg of gentamicin sulfate per milliliter may be used for serious systemic and genitourinary tract infections caused by Gram-negative bacteria, particularly Pseudomonas, Enterohacter, and Serratia spp. Because of the development of strains of these bacterial species resistant to previously effective broad-spectrum antibiotics, gentamicin has been used for the treatment of hospital-acquired infections caused by such organisms. however, appear to be emerging with increasing frequency With My Best Wishes NOOR AL-DABAGH 2017 5 Resistant bacterial strains that inactivate gentamicin b: acetylation) and