Kanamycins inactivation

New concepts in the strategy of the synthesis of drugs rarely appear, such as from the observation that microorganisms often get resistance from enqrmes that inactivate the drug through phosphorylation. To avoid the problem, the aminoglycoside antibiotic kanamycin A was modified in a way that it was re-obtained whenever it was modified by the microorganism resistance enzymes (Haddad 1999). 

It is semisynthetic derivative of kanamycin. It is active against gentamicin resistant organisms e.g. Pseudomonas aeruginosa, Klebsiella, E. coli and Proteus. It is resistant to bacterial aminoglycoside inactivating enzymes. 

Structures of several important aminoglycoside antibiotics. Ring II is 2-deoxystreptamine. The resemblance between kanamycin and amikacin and between gentamicin, netilmicin, and tobramycin can be seen. The circled numerals on the kanamycin molecule indicate points of attack of plasmid-mediated bacterial transferase enzymes that can inactivate this drug. , , and , acetyltransferase , phosphotransferase , adenylyltransferase. Amikacin is resistant to modification at , , , and . 

The use of marker genes that encode resistance lo clinically important antibiotics raises questions regarding whether the enzyme in the foot could inactivate oral doses of the antibiotic or whether die gene present in the plant DNA could be transferred lo pathogenic microbes in the GI tract or in soil rendering them resistant to treatment with the antibiotic, FDA evaluated these questions for the use of kanamycin resistance in tomato, cotton, canola,... 

Acetylation. Although modified by kanamycin acetyltransferase (Figure 7.10), complete inactivation of neomycin does not take place [46]. Thus, the acetylating enzyme plays no significant role in the resistance of Ps. aeruginosa to neomycin. 

Gentamicin is also a substrate for the enzyme kanamycin acetyltrans-ferase but is not inactivated by it. However, 6-N-acetylgentamicin Cia, the acylation product of gentamicin C,a by kanamycin acetyltransferase, can be acetylated by gentamicin acetyltransferase I. The resulting diacetate of gentamicin C,a is inactive as an antibiotic [46]. 

A second approach has been to acylate amino groups in the aminoglycoside molecule. The acylation of kanamycin with L(-)-4-amino-2-hydrox ybutyric acid has led to the synthesis of BB-K8 [222]. This compound, which is extremely active, fails to act as a substrate for any of the aminoglycoside inactivating enzymes produced by Ps. aeruginosa. However, it has recently been shown that BB-K8 is acetylated by a strain of E. coli [111]. 

For gentamycin derivatives, the introduction of an axial hydroxymethyl substituent at C-1 in the 2-deoxystreptamine moiety reportedly ameliorates nephrotoxicity and confers protection against inactivation by bacterial enzymes. The Belgium team investigated a similar modification in the kanamycin B series [265]. As expected, l-C-(hydroxymethyl)kanamycin B (212) proved equipotent with the parent aminoglycoside (208) against kanamycin B-sensitive bacteria and the introduction of a 6"-azido, 6"-chloro, or 6"-acetamido group (213)-(215), did not reduce antibacterial activity Table 3.19). However, the introduction of a l-C-(hydroxymethyl)... 

Amikacin is derived from kanamycin and has the broadest spectrum of activity of the aminoglycosides. It is less susceptible to bacterial enzyme inactivation than the other aminoglycosides, so it is usually reserved for therapy of gentamicin-resistant bacterial infections. 

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