Aminoglycoside antibiotics, enzymic

Enzymes transferring an acetyl moiety to one specific of several amino-groups of the aminocyclitol-aminoglycoside antibiotics (e.g. gentamicin, amikacin, kanamycin) are called aminoglycoside acetyltransferases... 

Beside AAC enzymes two different enzyme classes, nucleotidyltransferases (ANT enzymes), and phosphotransferases (APH enzymes) modify the hydroxyl groups of aminocyclitol-aminoglycoside antibiotics. 

Structure and Flexibility of Aminoglycoside Antibiotics Bound to Enzymes Involved in Bacterial Resistance... 

Vicens, Q. Westhof, E., Molecular recognition of aminoglycoside antibiotics by ribosomal RNA and resistance enzymes An analysis of x-ray crystal stmctures. 

In principle, various targets for therapeutic intervention exist. A successful drug can interact with viral receptors, virally encoded enzymes, viral structural components, viral genes or transcripts, or cellular factors required for viral replication. In recent years, attention has been given to small molecules that can target viral-specific RNA sites and prevent the formation of key RNA-protein and RNA-RNA complexes. Aminoglycoside antibiotics have provided the impetus for this approach as discussed below. 

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). 

Production of enzymes to degrade the antibiotic, e.g. novel (3-lactamases, extended-spectrum p-lactamases, or aminoglycoside-modifying 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 . 

Paromomycin sulfate is an aminoglycoside antibiotic that until recently was used in parasitology only for oral therapy of intestinal parasitic infections (see previous text). It has recently been developed for the treatment of visceral leishmaniasis. A phase 3 trial in India showed excellent efficacy for this disease, with a daily intramuscular dosage of 11 mg/kg for 21 days yielding a 95% cure rate, and noninferiority compared with amphotericin. The drug was registered for the treatment of visceral leishmaniasis in India in 2006. In initial studies, paromomycin was well tolerated, with common mild injection pain, uncommon ototoxicity and reversible liver enzyme elevations, and no nephrotoxicity. Paromomycin is much less expensive than liposomal amphotericin or miltefosine, the other promising new therapies for visceral leishmaniasis. 

The evolution of MRSA strains is not fully understood, but the same mechanisms of mutation and gene transfer that exist in other species provide a likely reason. The emergence of gentamicin resistance plasmids illustrates the evolutionary potential of translocatable elements [186], MRSA strains which are also resistant to this aminoglycoside antibiotic are referred to as MGRSA. This evolutionary progression is also responsible for the formation of the -lactamase-heavy metal resistant plasmids [250]. Some MRSA isolates are penicillin-resistant by virtue of the enzyme /J-lactamase, which pre-dates the use of /8-lactams [251], However, the spread of the phenotype has probably arisen as a result of selection caused by the widespread usage of methicillin in hospitals. 

Chloramphenicol (9) is liable to breakdown by chloramphenicol acetyl-transferases [185]. Fluoro derivatives (57, 58) resist enzymatic attack but little has been heard of these, apparently because of their toxicity [319], Aminoglycoside antibiotics (AGACs) may be chemically modified by AMEs. Some derivatives (e.g. amikacin, 43) are more recalcitrant than others, e.g. kanamycin (42) (see Figure 4.2). Other enzyme-resistant AGACs of low toxicity are needed. 

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.

Hon WC, McKay GA, Thompson PR, Sweet RM, Yang DS, Wright GD, Berghuis AM. Structure of an enzyme required for aminoglycoside antibiotic resistance reveals homology to eukaryotic protein kinases. Cell 1997 89 887-895. 

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