AMINOGLYCOSIDE RESISTANCE BY ENZYMATIC MODIFICATION
The aminoglycoside modifying enzymes are the most prevalent and clinically relevant mechanism of aminoglycoside antibiotic resistance. They are classified into three major families: the aminoglycoside N-acetyltransferases (AACs), the aminoglycoside O-nucleotidylyltransferases (ANTs), and the aminoglycoside O-phosphotransferases (APHs). These enzymes act by acetylating, adenylylating, or phosphorylating their target aminoglycosides on selected amino or hydroxyl groups using either acetylCoA or ATP as co-substrates.
The chemical groups that are affected by enzymatic modification are often directly involved in binding to the ribosome. For example, the 6 -amino group of the 2-deoxystreptamine aminoglycosides contacts A1408, and modification by acetylation alters the charge distribution and introduce a steric hindrance for productive complex formation.
The large number of these enzymes and associated genes discovered over the past 40 years has necessitated the establishment of a standardized nomenclature , which has been widely adopted. For example, the aminoglycoside resistance enzyme APH(3 )-IIIa is deciphered as “APH,” which refers to the enzyme family (aminoglycoside kinase), “(3 )” is the regiospecific site of modification on the antibiotic, “III” refers to the resistance phenotype (i.e., the individual aminoglycosides modified), and “a” is the specific gene. A partial list of known enzymes with their aminoglycoside resistance profiles is provided in Table 1.
TABLE 1. Aminoglycoside-Modifying Enzymes and Their Resistance Profiles
aA, amikacin; Ap,
apramycin; B, butirosin; D, dibekacin; G, gentamicin; H, hygromycin; I,
isepamicin; K, kanamycin; L, lividomycin; N, netilmicin; Ne, neomycin; P,
paromomycin; R, ribostamycin; S, sisomicin; Sp, spectinomycin; St, streptomycin;
Aminoglycoside-modifying enzymes have become widespread throughout bacterial communities because many of the encoding genes are found on mobile genetic elements such as integrons, transposons, and plasmids, which facilitate gene transfer among different species. Many organisms harbor chromosomally encoded aminoglycoside resistance genes such as Enterococcus faecium, which encodes an ubiquitous gene encoding the aminoglycoside acetyltransferase AAC(6 )-Ii . The result of the widespread gene dissemination is that almost every clinically important bacterial species is associated with aminoglycoside resistance.
The widespread dissemination of aminoglycoside-inactivating enzymes has contributed to the reduction in use of several aminoglycoside antibiotics. For example, the wide distribution of APH(3 ) enzymes have effectively made kanamycin clinically ineffective. The emergence of genes encoding ANT(2 ), AAC(3), and APH(2 ), is affacting gentamicin, one the few remaining aminoglycosides still in clinical use . These resistance genes are frequently clustered with other aminoglycoside resistance genes in Gram-negatives, conferring pan-aminoglycoside resistance in a single species . In gram-positive bacteria, the emergence of AAC(6 )-APH(2 ), a bifunctional enzyme that is able to modify almost every 2-deoxystreptamine aminoglycoside known, is also a significant concern.
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2, Costa, Y.; Galimand, M.; Leclercq, R.; Duval, J.; Courvalin, P. Antimicrob. Agents Chemother. 1993, 37, 1896.
3. Miller, G. H.; Sabatelli, F. J.; Hare, R. S.; Glupczynski, Y.; Mackey, P.; Shlaes, D.; Shimizu, K.; Shaw, K. J.; Groups, a. A. R. S. Clin. Infect. Dis. 1997, 24, S46.
4. Over, U.; Gur, D.; Unal, S.; Miller, G. H. Clin. Microbiol. Infect. 2001, 7, 470.
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