Aminoglycosides

Aminoglycosides are compounds that contain two or more amino sugars joined by glycoside bonds with an aminocyclitol ring (aglycon). The six-membered aminocyclitol ring is either streptidine (1,3-diguanidino-2,4,5,6-tetrahydroxycyclohexane), as in streptomycin, or 2-deoxystreptamine (1,3-diamino-4,5,6-trihydroxycyclohexane), as in all other aminoglycosides.

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2-Deoxystreptamine antibiotics can be further differentiated by the number and type of sugars bound to the aminocyclitol ring. Thus, neomycines, including neomycin itself and paro-momycin, have three sugar residues (two aminohexoses and one non-amino sugar pentose) bound to 2-deoxystreptamine. Analogs of kanamycin (kanamycin, tobramycin, amikacin) and gentamicin (gentamicin, sysomycin, netilmicin) each have two aminohexoses bound to the central aglycon. The last two series differ in the type of 3-aminohexoses. For a number of canamycines this is kanosamine, and for a number of gentamicines this is garosamine. Variations inside the aminoglycoside series themselves are caused by differences in the amino sugars and aglycon side chains.

Of the eight aminoglycosides that are currently used, five are synthesized from different versions of Streptomyces: streptomycin (isolated from Streptomyces griseus), neomycin (isolated from Streptomyces fradiae), paromomycin (isolated from S. rimosus), kanamycin (isolated from Streptomyces kanamyceticus), and tobramycin (isolated from

Streptomyces tenebrarius). Gentamicin is isolated from Micromonospora purpurea, and it consists of a mixture of approximately equal amounts of three compounds: gentamicines C1, C1a, and C2. Amikacin and netilmicin are semisynthetic drugs. Amikacin is a chemical modification of kanamycin. Netilmicin is a semisynthetic derivative of schizomycin, which is isolated from Micromonospora inyoensis.

Aminoglycoside antibiotics are bactericides. They inhibit protein synthesis and lead to incorrect reading of the genetic code. The common element in the process leading to the lethal outcome of bacteria is the active transfer of the drug from the surrounding medium into the bacterial cell, which leads to a large accumulation of medicine inside the cell exceeding that of the surroundings. Aminoglycosides easily diffuse through the outer membrane of the bacteria and enter the periplasmic space. The initial intracellular region of aminoglycoside action is the bacterial ribosome. There is evidently a minimum of two different types of ribosomal binding: one is specific to streptomycin, and the other acts by binding with other aminoglycosides. Streptomycin binds with the 30 S ribosomal subunit. Other aminoglycosides bind to different regions of 30 S and 50 S ribosomal subunits, and cannot compete with streptomycin for binding with 30 S ribosomes.

Binding between aminoglycosides and ribosomes is expressed as both direct inhibition of protein synthesis as well as incorrect reading of the genetic code from the matrix of mRNA, which leads to the insertion of incorrect amino acids into polypeptide chains. However, none of these effects fully explains the bactericidal effect of aminoglycosides. Aminoglycosides are drugs used predominantly against aerobic and a few Gram-negative microorganisms, S. aureus, and mycobacteria. These antibiotics are not active with respect to anaerobic microorganisms.

Bacterial resistance with respect to aminoglycosides can be explained by changes in binding regions on ribosomes, decline in intracellular transport, and deactivation of drugs by microbial enzymes.

Streptomycin binds with specific proteins (S12) on 30 S subunits of ribosomes. A change in this protein as a result of a mutation makes the ribosomes unable to bind with streptomycin, which makes the organism resistant. Mutational resistance to streptomycin occurs frequently. Gentamicin, tobramycin, netilmicin, and amikacin bind with many regions on both subunits of the ribosomes, and therefore mutational resistance to them is not common.

The second mechanism of resistance makes transport into the cell more difficult, which leads to resistance to all aminoglycosides. This type of resistance is not common among Gram-negative, aerobic, and a few other microorganisms. Since the transport of amino-glycosides through the cytoplasmic membrane is an oxygen-requiring process, anaerobic bacteria always exhibit resistance with respect to these bacteria.

The most important mechanism of resistance is the enzyme production by plasmids, which phosphorylate, adenylate, or acetylate specific amino or hydroxyl groups in the aminoglycoside molecules. These enzymes are not produced outside the cell. They are found in the periplasmic region. As soon as the drug passes through the outer membrane and reaches the perplasmic space, it undergoes a change by enzymes. The altered drug (along with the unchanged drug) competes for entrance into the cell, but it turns out that they are unable to bind with ribosomes. As a result, the energy-requiring phase of amino-glycoside uptake is inhibited. About 20 similar enzymes have been found. In turn, amino-glycosides differ in terms of their ability to resist enzymatic inactivation.

Gentamicin and tobramycin are sensitive to some of these same enzymes; netilmicin is somewhat more resistant to such enzyme modifications. Amikacin is the most resistant to the presently described enzymes. Gentamicin, tobramycin, netilmicin, and amikacin are effective in treating aerobic infections and other Gram-negative bacilli. In serious infections caused by P. aeruginosa, these drugs are used in combination with antibiotics with a broad spectrum, such as penicillin, ceftazidin, imipenem, or aztreonam. Streptomycin is the drug of choice for treating rabbit fever, plague, and brucellosis (in combination with tetracycline ). It is not used for treating other Gram-negative bacterial infections because of the high likelihood of developing resistance, which can develop as a result of only one mutation. However, it should be especially noted that practically all antibiotics of the aminoglycoside series are not metabolized in the body, but build up in the kidneys and have a certain oto- and nephrotoxicity.

Streptomycin: Streptomycin, irans-2,4-diguanidino-3,5,6-trihydroxycyclohexyl-5-deoxy-2-O-(2-deoxy-2-methylamino- a-L-glucopyranosyl)-3- C-hydroxymethyl-/¡-L-lyxo-pentofura-noside (32.4.1), is isolated from a culture liquid of the vital activity of the actinomycete S. griseus [238-247].

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