Aminoglycoside antibiotics modification

The preferred substrates of acetyltransferases are amino-groups of antibiotics, like chloramphenicol, strepto-gramin derivatives, and the various aminoglycosides. The modification is believed to block a functional group involved in the drug-target-interaction. All acetyltransferases use acetyl-coenzyme A as cofactor. 

The success of dibekacin prompted worldwide attention to the removal of selected OH groups in aminoglycoside antibiotics susceptible to modification by resistant bacteria, and the chemical deoxygenation procedure of D. H. R. Barton was found particularly useful. 

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 . 

Acetylation of antibiotics is a common mechanism of modification. The acyltransferases generally use the metabolically abundant acetyl-CoA as the preferred acyl-donor. The aminoglycoside antibiotic acetyltransferases (AACs), for example, modify important amines that make contact with the target 16 S rRNA (Fig. 9), which results in a loss of positive charge and increased steric bulk that contribute to lowering the affinity of the antibiotics for the rRNA target by 600-fold (26). The AACs are members of the GCN5 superfamily of acyltransferases that include such members as the eukaryotic histone acetyltransferases and serotonin acetyltransferase (27). 

Figure 9 Aminoglycoside antibiotic modifying enzymes. The aminoglycoside antibiotics such as kanamycin B (shown) bind to the 16 S rRNA of the bacterial ribosome impairing cognate codon-anticodon discrimination (A). Resistance occurs via acetylation (AAC), phosphorylation (APH), or adenylylation (ANT) of the antibiotic (B). A wide variety of enzymes are known with different regiospecificities of chemical modification, and the sites of some clinically important enzymes are shown in panel C.

This RNA-paromomycin structure also explains a number of features that help show why modification of the aminoglycoside antibiotic by the resistance enzymes prevents the modified drug from binding to the ribosomal site. These features are as follows. 

IV. TOTAL SYNTHESIS AND CHEMICAL MODIFICATION OF THE AMINOGLYCOSIDE ANTIBIOTICS... 

The 3"-A-acetylation of arbekacin 260 and amikacin 2, the first example of 3"-A-acetylation of aminoglycoside antibiotics by enzymatic modification, was reported in 1988. Subjection of kanamycin group antibiotics to an aminoglycoside 3-A-ace-... 

A variety of enzymatic mechanisms for antibiotic resistance are known. Hydrolysis of the lactam rings of /3-lactams, cephalosporins, and carbapenams destroys their ability to inhibit transpeptidases that cross-link peptidoglycan in bacterial cell walls. Modification of aminoglycoside antibiotics by acetylation, phosphorylation, or adenylation interferes with their ability to bind to the 16S subunit of the ribosome. Streptogramin activity can be destroyed by acetylation or by an elimination reaction that opens the lactone ring. The enzymes responsible for these detoxification reactions evolved in response to naturally occurring antibiotics, but are easily adapted to modify semisynthetic and completely synthetic antibiotics. For example, only a few point mutations are needed to enhance the ability of TEM /3-lactamases to hydrolyze third-generation cephalosporins such as cefotaxime and ceftazidime. ... 

Deoxy- and 6 -5"-dideoxyparomomycin 143, 144 were prepared from the pen-ta-N-benzyloxycarbonylparomomycin by reaction with tosylchloride, after separation of the two intermediates 6 -tosyl- and 6, 5"-ditosylparomomycin and subsequent reduction The importance of the 5"-hydroxyl group within the ribose containing aminoglycoside antibiotics (see ribostamycin) has been demonstrated by suitable modifications of lividomycin. 

III. 2.4.1 The Kammycins. Among the aminoglycoside antibiotics compounds of structural type 2 c play an important role in antibacterial chemotherapy. Great efforts have, therefore, been made to get new potent compounds of this class by fermentation or by chemical modification. 

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