Aminoglycosides Antibiotics 1

Introduction: Aminoglycosides are so named because their structures consist of amino sugars (glycone) linked glycosidically to aminocyclitol ring (aglycon). They are also called as Aminocyclitol antibiotics. They mainly act on Gram negative bacteria. (The gram-negative bacteria include the model organism Escherichia coli as well as many pathogenic bacteria, such as Pseudomonas aeruginosa, Neisseria gonorrhoeae, Chlamydia trachomatis, and Yersinia pestis) 2

They include Streptomycin, Amikacin, Gentamicin, kanamycin, Neomycin, Netilmicin, Paromomycin, Tobramycin. The first-in-class aminoglycoside antibiotic streptomycin. It is derived from Streptomyces griseus, the earliest modern agent used against tuberculosis Selman Waksman discovered "streptomycin," the first antibiotic active against tuberculosis in 1952, so he was warded the Nobel Prize. 3

Classification of Drugs Route of administration Topical use (eye/skin ) Neomycin Framycetin Gentamicin GIT Infection Neomycin Paromomycin Amikacin Systemic uses Streptomycin Nitilmicin Gentamicin Tobramycin Kanamycin 4

Aminocyclitol ring (aglycon) The aminocyclitol ring is 6M ring streptidine (1,3-diguanidino-2,4,5,6- tetrahydroxycyclohexane), in streptomycin, and 2-deoxystreptamine (1,3-diamino-4,5,6- trihydroxycyclohexane), in all other aminoglycosides.

As Amino cyclitols have several –OH, -NH2 these drugs have high water solubility. All aminoglycosides possess one or more amino sugar But some antibiotics like streptomycin, Neomycin, paramomycin possess a pentose sugar. Due to several amino group they are basic in nature and form salts with acids eg sulphate salts

Physico chemical properties They are water-soluble due to their polar groups (hydroxyl and amine groups), Stable in solution and more active at alkaline than at acid PH. Solutions remain stable for months Aminoglycosides frequently exhibit synergism with β-lactams or vancomycin. They concentrate at nephrone and inner ear (so toxicity for nephrone and ear) However, aminoglycosides may complex with β- lactam drugs, resulting in loss of activity and they should not be mixed together for administration.

Spectrum of Activity Although the aminoglycosides are as broadspectrum antibiotics. They are used in treatment of serious systemic infections caused by aerobic Gram-negative bacilli. The choice of agent is generally between kanamycin, gentamicin, tobramycin, netilmicin, and amikacin. Streptomycin is the most effective of the group for the chemotherapy of TB, brucellosis, tularemia, and Yersinia infections. Paromomycin is used primarily in the chemotherapy of amebic dysentery.

Streptomycin: It is isolated from streptomyces griseus. The aminocyclitol present is streptidine having 2 guanidino group responsible for basic nature It consist of two sugars Strptose (lyxose) N-methyl glucosamine This is called as streptobiosamine, attached by glycosidic linkage.

It is made of 3 basic structural units Streptidine (diguanidino gruop) Strptose (a aldose sugar) N-methyl-L- glucosamine The two guanidino groups have strong basic nature. The amino group in N-methyl-L- glucosamine is weakly basic It is available as streptomycin sulphate and streptomycin chloride.

SAR of  Modification on streptose has been extensively studied.  Reduction of –CHO group to alcohol form dihydrostreptomycin, activity similar to STM but produce severe deffness.  Oxd of –CHO to oxime, phenylhydrozone results inactive compoudns.  Oxd of –CH3 to –CH2-OH give active molecule but has no advantage over STM  N-methyl glucosamine is very essential for the activity.

 Modification of –NH2 CH3 group in glucosamine by demethylation & replace by large alkyl groups reduce activity.  In N-methyl glucosamine the nitrogen atom should be scondary amine.  Two guanido groups in streptidine ring are essential for activity, any changes reduce the activity.

MOA  The aminoglycoside antibiotics are rapidly bactericidal.  Bacterial killing is concentration-dependent  Inhibition of protein biosynthesis by binding to 30s portion of ribosomes.  Misreading of the mRNA codon, leading error in amin oacid sequencing(incorporation of incorrect amino acids into the growing polypeptide chains).  Inhibition of translocation of tRNA  Disruption of polymerase

Mechanism of action 14

Uses In TB leprosy Plague UTI Respiratory tract infection

Adverse reactions Severe ototoxicity Nephrotoxicity nephrotoxicity correlates with drug accumulation in the renal cortex Neuromuscular blockade Additional adverse reactions with administration of aminoglycosides may include: nausea, vomiting, anorexia, rash, and urticaria. 16