Antibiotics: Aminoglycosides

Antibiotics: Aminoglycosides The aminoglycoside antibiotics contain one or more amino sugars such as glucosamine linked by glycosidic linkages to a basic (amines or guanidine) six-membered carbon ring. These are broad-spectrum antibiotics; in general, they have greater activity against gram-negative than gram-positive bacteria. The aminoglycoside can produce severe adverse effects, which include nephrotoxicity, ototoxicity, and neuro effects. These properties have limited the use of aminoglycoside chemotherapy to systemic severe indications. Some aminoglycosides can be administered for ophthalmic and topical purposes.

Mode of action

The aminoglycosides exhibit bactericidal effects because of several phenomena. Ribosomal binding on the 30s and 50s subunits as well as the interface produces misreading; this disturbs normal protein synthesis. Cell membrane damage also plays an integral part in ensuring bacterial cell death.

Examples

Microbial resistance

The development of strains of Enterobacteriaceae resistant to antibiotics is a well-recognized, serious medical problem. Nosocomial (hospital-acquired) infections caused by these organisms are often resistant to antibiotic therapy. Research has established clearly that multidrug resistance among gram-negative bacilli to a variety of antibiotics occurs and can be transmitted to previously non-resistant strains of the same species of bacteria. Resistance is transferred from one bacterium to another by the extrachromosomal-R factor (DNA) that self-replicates and are transferred by conjugation (direct contact).

Treatment of Infections

Aminoglycoside antibiotics, because of their potent bactericidal action against gram-negative bacilli, are now preferred for the treatment of many serious infections caused by coliform bacteria. A pattern of bacterial resistance to each of the aminoglycoside antibiotics, however, has developed as their clinical use. Consequently, there are bacterial strains resistant to streptomycin, kanamycin, and gentamycin strains carrying R-factors for resistance to these antibiotics synthesize enzymes capable of acetylation, phosphorylating adenylating by amino or hydroxyl groups of aminoglycosides.

Resistance of individual aminoglycoside to specific inactivating enzymes can be understood, in large measure, by using clinical principles.

• First, one can assume that if the target functional group is absent in a position of the structure normally attacked by an inactivating enzyme then antibiotics will be resistant to the enzyme.
• Second, steric factors may confer resistance to attack at functionalities, otherwise susceptible to enzymatic attack. e. g conversion of a primary amine group to a secondary amine inhibits N-acetylation by certain aminoglycoside acetyltransferases.

At least nine different types of aminoglycoside-inactivating enzymes have been identified and partially characterized. Aminoglycoside-inactivating enzymes include amino acetyltransferases (ACC).

Details

• The gentamycin and tobramycin lack a 3’-hydroxyl group in ring-I and consequently are not inactivated by the phosphotransferase enzymes that phosphorylate that group in the kanamycin-B.
• Gentamycin-C is resistant to acetyltransferase that acetylates the 6’-amino group in ring-I of kanamycin-B.
• All gentamycin is resistant to the nucleotidyltransferase enzyme that adenylates to the secondary equatorial 4”-hydroxyl group of kanamycin because the 4”-hydroxyl (OH) group in gentamycin is tertiary and is oriented axially.
• Removal of functional groups susceptible to attacking an aminoglycoside occasionally can lead to derivatives that resist enzymatic inactivation and retain activity e. g 3’-deoxy, 4”-deoxy and 3’,4’, -dideoxykenamycins are more similar to the gentamycin and tobramycin in their pattern of activity against clinical isolate that resists one / more of the aminoglycoside inactivating enzyme.

 Amikacin

But the development of amikacin the 1-N-L-(-) amino-alpha-hydroxybutyric acid (L-AHBA) derivative of kanamycin keeps most of the intrinsic potency of kanamycin-A and is resistant to virtually all aminoglycoside inactivating enzyme known, except the amino-acetyltransferase that

1. Acetylates the 6’-amino group and the
2. Nucleotidyltransferase that adenylates the 4’-hydroxyl group of ring-I. the cause of amikacins resistance to enzymatic inactivation is not known, but it has been suggested that the introduction of the L-AHBA-group into the kanamycin-A markedly decreases its affinity for the inactivating enzyme.

Structure-activity relationship of kanamycin

It is convenient to discuss aminoglycoside SARs sequentially in terms of substituents in rings I, II, and III.

SAR of streptomycin

Streptodine

• Guanidine group act as antimicrobial and bacterial action against infection of the respiratory tract.
• If one of the guanidine groups is lost, there is a decrease in bacterial activity but an increase in toxicity.
• Due to the presence of two guanidine groups toxicity is decreased but no change in the therapeutic activity.
• When one of these two guanidine groups are converted into a urea group, toxicity is increased and loss of biological activity occurs. Similarly, if two groups are converted into urea, there is a future increase in toxicity and loss of biological activity.
• If guanidine groups are converted into a primary amine, no change in the biological activity but toxicity to the urinary bladder is increased.

Streptose group (5-C-sugar)

• If the aldehyde group at P-3 is converted into the keto group 50% of biological activity is lost.
• If the terminal CH3-group at P-4 is converted into primary alcohol, toxicity, and activity both fall. Such a compound having (-CH2OH group) at P-4 is called hydroxy-streptomycin which is also an active moiety. Similarly, if the aldehyde group at P-3 is also converted into CH3OH, the compound is called dihydrostreptomycin which has the same antimicrobial activity.

Glucosamine sugar

• If methyl amine at P-2 is converted into ethylamine (C2H5-NH-) toxicity of the compound is increased.
• If primary alcohol (-CH2OH) at P-4 is converted into other basic alkyl alcohol, absolute loss of activity occurs.

Streptomycin-B (mannosidostreptomycin)

It consists of a molecule of streptomycin-A linked glycosidically to D-mannose through 3,4-C hydroxy of N-methyl-L-glucosamine this means it consists of three sugars.

Streptomycin-C

This consist of a total of four sugar molecules.

Therapeutic uses

• Streptomycin is chiefly employed in the treatment of tuberculosis in conjunction with other drugs such as isoniazid and rifampicin.
• Streptomycin and penicillin exert a synergistic action against bacteria and are usually employed together in the treatment of subacute bacterial endocarditis caused by streptococcus faecalis.
• It exerts bacteriostatic action in low concentration and bacteriocidal in high concentration against a plethora of gram-negative and gram-positive organisms.
• A combination with tetracycline may be employed in the treatment of brucellosis and infection produced by pseudomonas mallei.

Toxicity

• Streptomycin causes very quick hemolysis, prolonged use of it, and causes the damaging to the VIII-cranial nerve which results in deafness. Either or both of the branches of the nerve may be involved. Damage to the auditory branch is associated with permanent impairment of the sense of hearing, and vestibular damage with equilibrium problems.