By far, aminoglycoside-modifying enzymes (AMEs) are the most common cause of aminoglycoside resistance. AMEs catalyze the covalent modification of aminoglycosides as they transport across the cytoplasmic membrane by modifying the amino or hydroxyl groups3. N-acetyltransferases (AAC) modify the –NH2 (amino) group by N-acetylation. Hydroxyl groups are modified by either O-nucleotidyltranferases (ANT) by O-nucleotidylation or O-phosphotranferases (APH) by O-phosphorylation. The acetylation, adenylation or phosphorylation of the aminoglycoside reduces drug binding to the ribosome, which results in high levels of resistance; it also negates the synergistic activity of the aminoglycoside with β-lactams. The level of resistance can also depend on the affinity of the specific aminoglycoside to the AME: the higher the affinity, the less amount of enzyme is needed to inactivate the aminoglycoside. AMEs are highly mobile and may be coded on the chromosome or spread by genes on plasmids and/or transposons. As a consequence, there is a broad range of bacteria that can support enzymatic resistance to aminoglycosides.7
Each enzyme is described by its class (AAC, ANT, or APH), a number in parentheses signifying the location of the modification of the drug, and a Roman numeral indicating a unique aminoglycoside resistance phenotype as they can differ greatly. Currently there are seven major clinically relevant phosphotransferases, four nucleotidyltransferases and four acetyltranferases (Table 2).3
Table2. Aminoglycoside resistance mechanisms – AMEs
| Resistance type | Enzyme subclass | Aminoglycoside inactivated | Bacteria affected |
|---|---|---|---|
| Phosphorylation Enzymes (APH) | |||
| Enzyme inactivation via phosphorylation of the aminoglycoside | APH(2”) | Kanamycin Tobramycin Gentamicin | Staphylococcus spp. Streptococcus spp. Enterococcus spp. |
| APH(3’) | Kanamycin Neomycin Amikacin | Enterobacteriaceae Pseudomonas spp. Staphylococcus spp. Streptococcus spp. Enterococcus spp. Corynebacterium spp. |
|
| APH(6) | Streptomycin | Gram negative organisms | |
| Acetylation Enzymes (AAC) | |||
| Enzyme inactivation via acetylation of the aminoglycoside | AAC(2’) | Gentamicin Tobramycin | Providencia spp. Proteus spp. Mycobacterium spp. |
| AAC(3’) | Kanamycin Tobramycin Gentamicin | Enterobacteriaceae Pseudomonas spp. |
|
| AAC(6’) | Kanamycin Tobramycin Amikacin | Enterobacteriaceae Pseudomonas spp. Staphylococcus spp. Enterococcus spp. |
|
| Adenylation Enzymes (ANT) | |||
| Enzyme inactivation via adenylation of the aminoglycoside | ANT(2”) | Kanamycin Tobramycin Gentamicin | Enterobacteriaceae Pseudomonas spp. |
| ANT(3”) | Streptomycin | Enterococcus spp. Pseudomonas spp. |
|
| ANT(4’) | Kanamycin Tobramycin Amikacin | Staphylococcus spp. Enterococcus spp. |
|
| ANT(6’) | Streptomycin | Wide spread amongst gram positive bacteria | |
| Bifunctional Enzymes | |||
| Enzymatic inactivation | AAC(6’)APH(2”) | Gentamicin Tobramycin Amikacin Kanamycin Arbekacin | Staphylococcus spp. Enterococcus spp. |
| AAC(6’)-Ib cr | Gentamicin Kanamycin Tobramycin Fluoroquinolones | Enterobacteriaceae | |
Source: Table adapted from Mandell, Douglas and Bennett. 2015. Molecular Mechanisms of Antibiotic Resistance in Bacteria. Principles and Practice of Infectious Diseases. Eighth Edition. Elsevier Saunders Philadelphia, PA. P242.
Recently, reports have described bi-functional enzymes that modify the structure of an entirely different class of antimicrobial agent (ciprofloxacin) as well as aminoglycosides. One such enzyme is designated as AAC(6’)-Ib-cr, which acetylates kanamycin, gentamicin and tobramycin, as well as the piperazinyl side group of ciprofloxacin3. Another recent development was the discovery of the bi-functional enzyme AAC(6’)APH(2”) with two functioning active sites (one for acetylation and the other for phosphorylation of aminoglycosides). This bi-functional enzyme is now readily seen in staphylococci and enterococci on a common transposon Tn4001 from transferable plasmids or on the chromosome, and confers high levels of resistance to the aminoglycosides.3
