Aminoglycoside antibiotic resistance
Resistance to aminoglycosides results largely from interference with the drug transport mechanism following modification of the antibiotic by one or more of a series of enzymes produced by the resistant bacteria. Such aminoglycoside-modifying enzymes are often plasmid-encoded, but have been associated increasingly with the presence of transposons and integrons. The first reports of enzyme-mediated aminoglycoside resistance were published by Umezawa’s group in the 1960s,[1-2] and were preluding to an international emergence of high-level aminoglycoside resistance that has been largely spread via R-plasmids, transposons, and integrons. This emergence of transferable aminoglycoside antibiotic resistance spurred the search and development of new natural product and semisynthetic aminoglycoside drugs that retained antimicrobial activity in the face of resistance. Thus the natural product tobramycin and the semisynthetic derivative of kanamycin B, amikacin, were introduced in the early 1970s. Since the clinical introduction of these compounds, only a limited number of aminoglycosides were successfully introduced into the clinic, mostly in Japan, in response to the emergence of resistance. The most successful of these were isepamicin and arbekacin.
The molecular details of resistance to aminoglycosides have been explored intensively. These are understood at atomic resolution thanks to the determination of co-complex structures of aminoglycosides with the ribosome and model RNAs . Aminoglycoside resistance occurs by three methods:
(1) modification of the rRNA and ribosomalprotein targets,
(2) modification of aminoglycoside transport (import and efflux), and
(3) via the synthesis of aminoglycoside-modifying enzymes.
The latter have been the most prevalent mechanism in most clinical isolates of resistant bacteria, but the other mechanisms are now emerging as more important especially in niche settings and organisms. Table 1 reports the most common aminoglycoside-modifying enzymes and their characteristic substrates.
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;
OVERCOMING AMINOGLYCOSIDE RESISTANCE
The impact of aminoglycoside resistance
on the use of these bactericidal antibiotics has been significant. They have
been eclipsed by other classes less prone to preexisting resistance and with
improved pharmacological properties. The emergence of resistance to other
antibiotic classes, the value of bactericidal agents in the treatment of immune
compromised patients, the availability of detailed information on the
Inhibition of Aminoglycoside Resistance Enzymes
A small-molecule inhibitor of an aminoglycoside-inactivating enzyme could reverse resistance by blocking the activity of the resistance enzyme and thereby rescue antibiotic activity in the face of resistance. The inhibitory activity of 7-hydroxytropolone on ANT(2 ) was reported and shown to potentiate aminoglycosides in resistant strains , however this was neither sufficiently selective nor biologically active to be therapeutically interesting.
A challenge in the design of
aminoglycoside potentiating agents is the large number of resistance mechanisms
that exist in the clinic. The
Intrinsically resistant aminoglycosides
The number of aminoglycoside antibiotic resistance strategies and associated genes means that truly intrinsically resistant aminoglycosides are likely to remain a dream. recent semisynthetic approaches have significantly expanded the chemical diversity of the class with opportunities to explore new activities. For example, the natural products tobramycin and gentamicin lack 3 -hydroxyl groups and are thus not susceptible to APH(3 ) enzymes. The semisynthetic compound amikacin (4-amino-2-hydroxybutrylamide derivative of kanamycin), which was inspired by the natural product butirosin, has improved activity against aminoglycoside resistant-strains. Efforts to expand chemical diversity have been rather successful. For example, neamine dimers maintained good antibiotic activity and inhibited APH(2 ) activity . A new class of semisynthetic derivatives of neamine, termed the pyranmycins, with excellent antibiotic activity including against resistant strains has been reported [7-8]. In a similar work, a library of kanamycin derivatives has been prepared, providing several compounds showing excellent bioactivity and demonstrating the ability to greatly expand the chemical space of these compounds .
The structure-based drug design has allowed to rationally designed semisynthetic antibiotic using the crystal structure of the 30S ribosomal subunit as a guide . Similarly, by comparing the binding of aminoglycosides to resistance enzymes and 16S rRNA in silico lead to the design of conformationally restricted aminoglycosides that would favor rRNA binding over resistance enzymes resulting in retained antibiotic activity even in the presence of resistance genes .
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