Streptomycin History. Streptomycin was discovered in 1944 as a fermentation product of Streptomyces griseus (254). It belongs to the family of aminoglycoside antibiotics, which includes kanamycin, gentamicin, neomycin, amikacin, nebramycin, paromomycin, ribosta-mycin, tobramycin, sisomicin, dibekĀ§.cin, netilmicin, kasugamycin, and spectinomycin. In terms of chemical structure, they are ami-nocyclitols (cyclohexane with hydroxyl and amino or guanidino substituents) with glyco-syl substituents at one or more hydroxyl groups. Streptomycin is an N-methyl-L-glu-cosaminidostreptosidostreptidine made up cf three components: streptidine, streptose, and N-methyl-L-glucosamine (38).The intact molecule is necessary for antibacterial action.

Mannosidostreptomycin (39) is another antibiotic, produced together with streptomycin by S. griseus, which has not found clinical application because it is less active than streptomycin itself. Hydroxystreptomycin (40), produced by S. griseocarneus, has biological properties similar to those of streptomycin, with no advantages over it.

In the attempt to improve activity and/or decrease toxicity of streptomycin, some chemical modifications have been performed (e.g., on aldehyde or guanidino functions), which yielded generally less active

products. One chemical derivative of streptomycin, dihydrostreptomycin (41), obtained by catalytic hydrogenation of the carbonyl group of streptose, has almost the same antibacterial activity of the parent compound and investigators hoped that it would differ from the parent in having lower toxicity. Later clinical experience did not confirm this hope. Activity and Mechanism of Action. Streptomycin is both bacteriostatic and bactericidal for the tubercle bacillus in vitro, according to the concentration of the antibiotic. Concentrations of streptomycin around 1 fig/mL inhibit the growth of M. tuberculosis H37Rv. NTM are not susceptible to streptomycin. The antibacterial activity of streptomycin is not restricted to M. tuberculosis but includes a variety of Gram-positive and Gram-

negative bacteria. The most important clinical use of streptomycin is in the therapy of tuberculosis and it was the first really effective drug for this disease. Its importance declined after the introduction of other powerful oral antitu-berculous agents. Since the introduction of other broad-spectrum antibiotics, the use of streptomycin in the treatment of infections is limited to diseases in which other alternatives are lacking and the sensitivity of the infecting organism indicates the choice and eventually the use of this drug in combination with other antibiotics. Thus, it is still a drug of first choice for enterococcal endocarditis (in combination with penicillin or ampicillin), in brucellosis (in combination with tetracycline), in plague, and in tularemia.

The investigation on the mechanism of action of streptomycin has involved a number of elegant studies in microbiological chemistry and molecular biology that have led to a succession of hypotheses and to a continuous increase in knowledge not only of the mode of action of the antibiotic but also of the biology of the bacteria. After a series of preliminary hypotheses, it was finally ascertained that the drug is a specific inhibitor of protein biosynthesis in intact bacteria (255, 256). The ribo-some, and particularly its 30S subunit, is the site of action of the antibiotic (257,258), and after careful disassemble of 30S ribosomes, a protein designated P10 was determined to be the genetic locus responsible for the pheno-typic expression of sensitivity and resistance and dependence on streptomycin (259). The antibiotic induces a misreading of the genetic code, demonstrated through studies of the erroneous incorporation of amino acids in cellfree ribosome systems (260). It was deduced that the misreading in vivo was the cause of the bactericidal effect of streptomycin, because it resulted in "flooding the cell" with erroneous, non-functional proteins. However, it was subsequently demonstrated that this could not be the case because in the intact bacteria the antibiotic inhibits the synthesis of proteins (261). The ultimate mode by which streptomycin exerts its bactericidal activity is not yet clear. Two hypotheses have been put one suggesting that streptomycin specifically inhibits initiation of protein synthesis (262) (this is supported by the involve ment of protein P10, the site of action of streptomycin, in the initiation reaction) and the other suggesting that it inhibits peptide chain elongation, that is, the synthesis of peptide bonds at any time during the growth of the peptide chain (263,264).As noted before, sensitivity and resistance to and dependence on streptomycin all seem to be expressed in the ribosome and apparently are multiple alleles of a single genetic locus. Streptomycin-resistant mutant cells arise spontaneously in a bacterial culture, with a frequency of the order 1-10 6 (265).

In the phenomenon of streptomycin dependence, bacteria require streptomycin to grow; these bacteria also arise by spontaneous mutation (266), and the mechanism of their behavior is also related to the reading of codons. This can be done correctly only in the presence of streptomycin, which overcomes an undis-criminating restriction (caused by mutation), leading to a mutant in which the ribosomal screen does not allow normal translation for growth (261-267). In addition, resistance to streptomycin can be transferred by means of R-factors or plasmids, namely, by extra-chromosomal DNA carrying multiple antibiotic resistance (268).

The mode of transmission of resistance is particularly frequent among enterobacteria. Enzymatic inactivation is a frequent cause of resistance to streptomycin in eubacteria. The aminoglycoside-inactivating enzymes are phosphotransferases, acetyl-transferases, and ade-nyl-transferases. Because they act by inactivating a chemical group that is common to different aminoglycosides, bacterial strains that produce only one of them can be resistant to all aminoglycosides possessing the same chemical group (cross-resistance). Streptomycin can be inactivated by some streptomycin-adenyltransferase and streptomycin-phospho-transferase, which usually do not affect other aminoglycosides except spectinomycin (172).

In mycobacteria, mutations in the rpsL gene, which encodes the ribosomal protein S12 have been shown to confer resistance to streptomycin. Analysis of the primary structure of the ribosomal protein S12 in M. tuberculosis has revealed that mutations in the gene replacing Lys43 or Lys88 by arginine are frequently associated with resistance to strep tomycin (269-272).A second type of mutation conferring resistance has been identified in streptomycin-resistant strains of M. tuberculosis that have a wild-type rpsL gene. These strains have point mutations in the 16S rRNA clustered in two regions around nucleotides 530 and 915 (273,274).In those isolates with a wild-type 16S rRNA and rpsL gene, other mechanism of drug resistance can be hypothesized, such as modifications of other components of the ribosome or alteration in cellular permeability. Pharmacokinetics. Streptomycin, like all other aminoglycoside antibiotics, is not absorbed from the gastrointestinal tract, and therefore, it must be administered parenter-ally. Serum peak levels are reached in 1-2 h, and the values are 9-15 jag/mL after administration of 1 g. Its half-life is 2-3 h. The serum protein binding of streptomycin is 25-35% (275). Streptomycin diffuses slowly into the pleura and better into the peritoneal, pericardial, and synovial fluids. It does not penetrate into spinal fluid, unless the meninges are inflamed. Urinary elimination is rapid, and 70% of the drug is excreted in unmodified form in the first 24 h. Adverse Effects. The most important toxic effects of streptomycin involve the peripheral and central nervous system. The eighth cranial nerve is the most frequently injured by prolonged administration of streptomycin, especially in its vestibular portion, causing equilibrium disturbances to appear. Treatment with 2-3 g/day for 2-4 months produces this type of side effect in about 75% of patients, but the incidence is much less at doses of 1 g/day. Other side effects are hypersensitivity reactions and renal damage.

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