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Aminoglycosides: An Overview
Kevin M. Krause,1Alisa W. Serio,1Timothy R. Kane,1and Lynn E. Connolly1,2
1
Achaogen, South San Francisco, California 94080
2
Department of Medicine, Division of Infectious Diseases, University of California, San Francisco,
San Francisco, California 94143
Correspondence: kevinmichaelkrause@gmail.com
Aminoglycosides are natural or semisynthetic antibiotics derived from actinomycetes.
They were among the first antibiotics to be introduced for routine clinical use and several
examples have been approved for use in humans. They found widespread use as first-line
agents in the early days of antimicrobial chemotherapy, but were eventually replaced in the
1980s with cephalosporins, carbapenems, and fluoroquinolones. Aminoglycosides syner-
gize with a variety of other antibacterial classes, which, in combination with the continued
increase in the rise of multidrug-resistant bacteria and the potential to improve the safety and
efficacy of the classthrough optimized dosing regimens, has led to a renewed interest in these
broad-spectrum and rapidly bactericidal antibacterials.
Aminoglycosides are potent, broad-spectrum
antibiotics that act through inhibition of
protein synthesis. The class has been a corner-
stone of antibacterial chemotherapy since strep-
tomycin (Fig. 1) was first isolated from Strepto-
myces griseus and introduced into clinical use
in 1944. Several other members of the class
(Fig. 1) were introduced over the intervening
years including neomycin (1949, S. fradiae),
kanamycin (1957, S. kanamyceticus), gentami-
cin (1963, Micromonospora purpurea), netilmi-
cin (1967, derived from sisomicin), tobramycin
(1967, S. tenebrarius), and amikacin (1972, de-
rived from kanamycin). A shift away from sys-
temic use of the class began in the 1980s with
the availability of the third-generation cepha-
losporins, carbapenems, and fluoroquinolones,
which were perceived to be less toxic and/or
provide broader coverage than the aminoglyco-
sides. However, increasing resistance to these
classes of drugs, combined with more exten-
sive knowledge of the basis of aminoglycoside
resistance, has led to renewed interest in the
legacy aminoglycosides and the development
of novel aminoglycosides such as arbekacin
and plazomicin (Fig. 4). These latter agents
were designed to overcome common amino-
glycoside resistance mechanisms thereby main-
taining potency against multidrug-resistant
(MDR) pathogens.
Additionally, improved dosing schemes
have been developed that attempt to reduce
aminoglycoside toxicity while maintaining effi-
cacy. Specifically, clinical studies have reported
a lower incidence of nephrotoxicity with once-
daily dosing (Nicolau et al. 1995). These data
Editors: Lynn L. Silver and Karen Bush
Additional Perspectives on Antibiotics and Antibiotic Resistance available at www.perspectivesinmedicine.org
Copyright #2016 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a027029
Cite this article as Cold Spring Harb Perspect Med 2016;6:a027029
1
www.perspectivesinmedicine.org
are consistent with the concept that higher dos-
es given less often should reduce the risk of tox-
icity while maintaining and possibly enhancing
efficacy (Drusano et al. 2007). The advantages
of once-daily dosing of aminoglycosides are
now widely accepted and, for many infection
types, this dosing schedule has become the stan-
dard of care (Avent et al. 2011). Additionally,
inhaled delivery of aminog lycosides has become
an area of renewed interest because it allows for
greater local exposure within the lungs with re-
duced systemic toxicity. Inhaled tobramycin is
available in the European Union (EU) and the
United States for the treatment of patients with
chronic Pseudomonas aeruginosa lung infection
associated with cystic fibrosis (CF), and inhaled
amikacin and arbekacin are in development for
potential use in CF and acute respiratory tract
infections.
SPECTRUM OF ACTIVITY
Aminoglycosides are active against various
Gram-positive and Gram-negative organisms.
Streptomycin Apramycin
Amikacin Neomycin B
Gentamicin C1a
Tobramycin
HO
HO
HO
OH
OH
OH
OH
NH
NH
HN
NH2
H2N
N
O
O
O
O
O
H
N
H
HO
HO O
OO
O
H
H
HN
OH
OH
OH
OH
NH2
H2NNH2
H2N
HO
HO
H2NH2N
H2N
NH2
NH2
O
O
OH
OH
OH
O
O
H2NH2NNH2
NH2HO
OH
HN
O
OO
O
OH
H2N
H2N
OH
NH2
H2NNH
O
OH
OH
OH
OH
HO
HO
HO
O
O
O
O
HO OH
OH
OH
OH
HO
HO
O
O
O
O
O
O
H2NH2N
NH2
NH2
NH2
NH2
O
Figure 1. Structures of representative aminoglycosides, including the atypical aminoglycosides streptomycin and
apramycin, 4,6-substituted AGs tobramycin, gentamcin, and amikacin, and the 4,5-substituted AG neomycin.
The deoxystreptamine or streptidine rings are in bold.
K.M. Krause et al.
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Aminoglycosides are particularly potent against
members of the Enterobacteriaceae family, in-
cluding Escherichia coli,Klebsiella pneumoniae
and K.oxytoca,Enterobacter cloacae and E.
aerogenes,Providencia spp., Proteus spp., Mor-
ganella spp., and Serratia spp. (Ristuccia and
Cunha 1985; Aggen et al. 2010; Landman et al.
2010). Furthermore, aminoglycosides are ac-
tive against Yersinia pestis (Heine 2015) and
Francisella tularensis (Ika
¨heimo et al. 2000),
the causative agents of plague and tularemia,
respectively. The class also has good activity
against Staphylococcus aureus, including meth-
icillin-resistant and vancomycin-intermediate
and -resistant isolates, P. aeruginosa and to a
lesser extent Acinetobacter baumannii (Ristuc-
cia and Cunha 1985; Karlowsky et al. 2003;
Aggen et al. 2010; Landman et al. 2011).
Many Mycobacterium spp. are also susceptible
to aminoglycosides including Mycobacterium
tuberculosis,M. fortuitum,M. chelonae, and
M. avium (Swenson et al. 1985; Ho et al.
1997).
Active electron transport is required for ami-
noglycoside uptake into cells, so the class inher-
ently lacks activity against anaerobic bacteria
(Kislak 1972; Martin et al. 1972; Ramirez and
Tolmasky 2010). Aminoglycosides are also inac-
tive against most Burkholderia spp. and Steno-
trophomonas spp. as well as Streptococcus spp.
and Enterococcus spp. (Brogden et al. 1976; Va-
kulenko and Mobashery 2003; Brooke 2012;
Podnecky et al. 2015).
Contemporary large-scale surveillance pro-
grams provide an understanding of current
aminoglycoside susceptibility among impor-
tant pathogens associated with common infec-
tion types. A recent surveillance study of Gram-
negative organisms isolated from patients
hospitalized in intensive care units (ICUs) in
the United States and the EU found that ami-
kacin and gentamicin showed good activity
against key Gram-negative pathogens (Sader
et al. 2014). In the United States, 99.5% and
87.9% of E. coli isolates were susceptible to ami-
kacin and gentamicin, respectively, according to
the Clinical and Laboratory Standards Institute
(CLSI) criteria. Likewise, 97.3% and 87.2% of
E. coli isolates from the EU were susceptible to
amikacin and gentamicin, respectively, accord-
ing to the European Committee on Antimicro-
bial Susceptibility Testing (EUCAST) criteria.
Among Klebsiella spp., 94.8% and 92.7% of
U.S. isolates and 90.5% and 83.3% of EU
isolates were susceptible to amikacin and gen-
tamicin, respectively. Amikacin was one of
the few agents that retained activity against P.
aeruginosa (97.3% susceptibility in the United
States and 84.9% in the EU according to CLSI
and EUCAST criteria, respectively). Similarly,
aminoglycoside susceptibility rates were high
among isolates collected from U.S. medical cen-
ters in 2012 (Sader et al. 2015). In this study,
CLSI-based susceptibility rates were 99.0%,
88.2%, and 86.3% among E. coli and 88.2%,
89.2%, and 82.4% against K. pneumoniae for
amikacin, gentamicin, and tobramycin, respec-
tively. However, activity was reduced among
K. pneumoniae carbapenemase (KPC)-produc-
ing K. pneumoniae, which are often resistant to
multiple classes of drugs, for amikacin (42.5%
susceptible), gentamicin (50.0% susceptible),
and tobramycin (25.0% susceptible). Amikacin
was the most active agent tested against P. aer-
uginosa (98% susceptible), followed closely by
tobramycin (90% susceptible) and gentamicin
(88.0% susceptible). Broad potency was also
observed against S. aureus (96.0%, 95.0%, and
76.0% for amikacin, gentamicin, and tobramy-
cin, respectively), but these compounds were
less active against A. baumannii (58.0% sus-
ceptible).
The broad-spectrum activity of amino-
glycosides is enhanced in vitro through synergy
with other classes of antimicrobials. This phe-
nomenon, in which the combined effect of
two antimicrobial agents is greater than the
sum of their individual effects, is particularly
well characterized between aminoglycosides
and cell-wall-active agents such as b-lactams.
In vitro synergy between aminoglycosides
and b-lactams has been observed in both
Gram-negative and -positive organisms, in-
cluding wild-type and MDR isolates, using a
variety of methodologies (Eliopoulos and Eli-
opoulos 1988). These in vitro observations
have helped to stimulate the use of aminogly-
coside-containing combination therapy in the
Aminoglycosides: An Overview
Cite this article as Cold Spring Harb Perspect Med 2016;6:a027029 3
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treatment of a number of infection types (see
below).
MECHANISM OF ACTION
Aminoglycosides inhibit protein synthesis by
binding, with high affinity, to the A-site on
the 16S ribosomal RNA of the 30S ribosome
(Kotra et al. 2000). Although aminoglycoside
class members have a different specificity for
different regions on the A-site, all alter its con-
formation. As a result of this interaction, the
antibiotic promotes mistranslation by inducing
codon misreading on delivery of the aminoacyl
transfer RNA. This results in error prone pro-
tein synthesis, allowing for incorrect amino
acids to assemble into a polypeptide that is sub-
sequently released to cause damage to the cell
membrane and elsewhere (Davis et al. 1986;
Mingeot-Leclercq et al. 1999; Ramirez and
Tolmasky 2010; Wilson 2014). Some aminogly-
cosides can also impact protein synthesis by
blocking elongation or by directly inhibiting
initiation (Davis 1987; Kotra et al. 2000; Wilson
2014). The exact mechanism of binding and the
subsequent downstream effects varies by chem-
ical structure, but all aminoglycosides are rap-
idly bactericidal (Davis 1987; Mingeot-Leclercq
et al. 1999) and typically produce a prolonged
postantibiotic effect (PAE) (Zhanel et al. 1991)
The PAE has been shown to be directly related
to the length of time that the bacteria take
to recover from the inhibition of protein syn-
thesis (Stubbings et al. 2006). It is hypothesized
that this is dependent on the eventual disasso-
ciation of the antibiotic from its target and exit
from the cell.
Aminoglycosides are characterized by a core
structure of amino sugars connected via glyco-
sidic linkages to a dibasic aminocyclitol, which
is most commonly 2-deoxystreptamine (Min-
geot-Leclercq et al. 1999). Aminoglycosides
are broadly classified into four subclasses based
on the identity of the aminocyclitol moiety:
(1) no deoxystreptamine (e.g., streptomycin,
which has a streptidine ring); (2) a mono-sub-
stituted deoxystreptamine ring (e.g., apramy-
cin); (3) a 4,5-di-substituted deoxystreptamine
ring (e.g., neomycin, ribostamycin); or (4) a
4,6-di-substituted deoxystreptamine ring (e.g.,
gentamicin, amikacin, tobramycin, and plazo-
micin) (Magnet and Blanchard 2005; Wachino
and Arakawa 2012). Examples of each subclass
are shown in Figure 1. The core structure is
decorated with a variety of amino and hydroxyl
substitutions that have a direct influence on
the mechanisms of action and susceptibility
to various aminoglycoside-modifying enzymes
(AMEs) associated with each of the aminogly-
cosides.
Aminoglycoside entry into bacterial cells is
comprised of three distinct stages, the first of
which increases permeability of the bacterial
membrane, whereas the second and third are
energy-dependent. The first stage involves elec-
trostatic binding of the polycationic aminogly-
coside to the negatively charged components
of the bacterial membrane, such as the phos-
pholipids and teichoic acids of Gram-positive
organisms and the phospholipids and lipopoly-
saccharide (LPS) of Gram-negative organisms,
followed by displacement of magnesium ions
(Davis 1987; Taber et al. 1987; Ramirez and Tol-
masky 2010). These cations are responsible for
cross bridging and stabilization of the lipid
components of the bacterial membrane and
their removal leads to disruption of the outer
membrane, enhanced permeability, and initia-
tion of aminoglycoside uptake (Hancock et al.
1981, 1991; Hancock 1984; Ramirez and Tol-
masky 2010). This phenomenon facilitates
entry into the cytoplasm via a slow, energy-de-
pendent, electron-transport-mediated process
(Kislak 1972; Martin et al. 1972; Davis 1987;
Taber et al. 1987; Ramirez and Tolmasky
2010). Inhibition of protein synthesis and mis-
translation of proteins occurs once aminogly-
coside molecules access the cytoplasm. These
mistranslated proteins insert into and cause
damage to the cytoplasmic membrane itself
and facilitate subsequent aminoglycoside entry
(Nichols and Young 1985; Davis et al. 1986).
This then leads to rapid uptake of additional
aminoglycoside molecules into the cytoplasm,
increased inhibition of protein synthesis, mis-
translation, and accelerated cell death (Davis
et al. 1986; Davis 1987; Taber et al. 1987; Ra-
mirez and Tolmasky 2010).
K.M. Krause et al.
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MECHANISMS OF AMINOGLYCOSIDE
RESISTANCE
Aminoglycoside resistance takes many different
forms including enzymatic modification, target
site modification via an enzyme or chromosom-
al mutation, and efflux. Each of these mecha-
nisms has varying effects on different members
of the class and often multiple mechanisms are
involved in any given resistant isolate. Resis-
tance to aminoglycosides via target site muta-
tions has not been observed because nearly all
prokaryotes, with the exception of Mycobacteri-
um spp. (Bercovier et al. 1986) and Borrelia spp.
(Schwartz et al. 1992), encode multiple copies
of rRNA. Although contemporary large-scale
surveillance programs provide an understand-
ing of phenotypic aminoglycoside resistance
among important pathogens, these studies
have generally not focused on the epidemiology
of specific resistance mechanisms (Jones et al.
2014; Sader et al. 2015).
Enzymatic Drug Modification
AMEs are often found on plasmids containing
multiple resistance elements, including other
AMEs or b-lactamases. The mobility of these
enzymes might be tied to their origins, which
has been hypothesized to be via horizontal gene
transfer from the actinomycetes responsible
for the natural production of aminoglycosides
(Shaw et al. 1993; Ramirez and Tolmasky 2010).
More than 100 AMEs have been described and
are broadly categorized into three groups based
on their ability to acetylate, phosphorylate, or
adenylate amino or hydroxyl groups found at
various positions around the aminoglycoside
core scaffold (Ramirez and Tolmasky 2010).
These modifications decrease the binding affin-
ity of the drug for its target and lead to a loss in
antibacterial potency (Llano-Sotelo et al. 2002).
These three families of AMEs include ami-
noglycoside N-acetyltransferases (abbreviated
AACs), aminoglycoside O-nucleotidyltransfer-
ases (ANTs), and aminoglycoside O-phospho-
transferases (APHs). The classes are further di-
vided into subtypes according to the position
on the aminoglycoside that the enzyme modi-
fies followed by a Roman numeral and, in some
cases, a letter when multiple enzymes exist that
modify the same position (Shaw et al. 1993;
Ramirez and Tolmasky 2010). The major sites
of aminoglycoside modification for the most
common AMEs are shown for kanamycin A in
Figure 2.
Aminoglycoside Acetyltransferases
The aminoglycoside acetyltransferases or AACs
comprise the largest group of AMEs. They are
part of the GCN5-related N-acetyltransferase
(GNAT) superfamily of 10,000 described pro-
teins (Ramirez and Tolmasky 2010). These en-
zymes acetylate amino groups found at various
positions on the aminoglycoside scaffold in
an acetyl-CoA-dependent reaction (Fig. 3A).
There are four main subclasses of this group
OH
OH
OH
HO HO
O
H2NH2NNH2
N1
6′′
4′′
3′′
2′
5
AAC(3)AAC(6′)
H2N
OO
O
OH
HO
ANT(4′)
APH(3′)ANT(2′′)
Figure 2. Sites of chemical modification by representative aminoglycoside-modifying enzymes (AMEs) on
kanamycin A.
Aminoglycosides: An Overview
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of enzymes whose nomenclature is derived
from the specific amino group that is modified.
Specifically, AAC(1) and AAC(3) target the ami-
no groups found at position 1 and 3, respective-
ly, of the 2-deoxystreptamine ring, whereas
AAC(20) and AAC(60) target amino groups
found at the 20and 60position of the 2,6-di-
deoxy-2,6-diaminoglucose ring (Mingeot-Le-
clercq et al. 1999; Wright and Thompson 1999;
Azucena and Mobashery 2001; Magnet and
Blanchard 2005).
A representative of the AAC family
(AAC(60)-IV) was the first AME found in bac-
teria to be described in the literature (Okamoto
and Suzuki 1965). Since then, .70 members
of the AAC family have been described. Fre-
quently observed class members found among
Gram-negative bacteria include the AAC(60)-1
enzyme that leads to amikacin, netilmicin, and
tobramycin resistance, AAC(3)-IIa, which is
responsible for resistance to gentamicin, tobra-
mycin, and netilmicin, and AAC(3)-I, which
modifies gentamicin (Shaw et al. 1993; Cas-
tanheira et al. 2015). Less common are the
AAC(60)-APH(200) hybrid enzyme responsible
for high-level aminoglycoside resistance in
Enterococcus faecalis (Culebras and Martı
´nez
1999), the chromosomally encoded AAC(60)-
Ii enzyme responsible for intrinsic resistance
to aminoglycosides among E. faecium (Costa
et al. 1993) and the chromosomal AAC(20) en-
zyme found in Mycobacterium spp. and Provi-
OH
OH
O
O
O
OOO
HO
HN
OH
HN
OH
O
O
O
OH
NH2
H2NH2N
A
B
C
H2NNH2
NH2
NH2Acetyl-CoA CoA
HO
HN
NH
NH2
ATP ADP
HO
HO
O
OO
O
NH
O
OH
OH
OH
OH
OH
O
O
P
–O
–O
O
O
O
H2NH2NH2N
NH2
H2N
H2N
H2N
H2N
H2N
H2N
H2NH2N
H2N
NH2
NH2
HO
HO HO
OH
OH
OH
NN
N
NO
O
O
O
OO
O
O
O–
P
HO
HO
HO
OH
OH
OH
OH
OH
ATP PPi
ANT(2′′)
OH
O
OO
O
H2N
O
O
OH
HO HO
HO
OH OH
APH(3′)
AAC(3)
OH
Figure 3. Examples of aminoglycoside modification by AMEs. (A) An example of chemical modification of
gentamicin catalyzed by the aminoglycoside acetyltransferase AAC(3). (B) An example of chemical modification
catalyzed by the aminoglycoside phosphotransferase APH(30) on amikacin. (C) Adenylation of the 200 hydroxyl
of kanamycin A catalyzed by the aminoglycoside nucleotidyltransferase ANT(200).
K.M. Krause et al.
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dencia stuartii (Rather et al. 1993; Aı
´nsa et al.
1997; Macinga and Rather 1999; Ramirez and
Tolmasky 2010). Last, a variant of AAC(60)-Ib
that has acquired the ability to modify fluoro-
quinolones without significantly altering its
activity against aminoglycosides has been iden-
tified in clinical isolates of Gram-negative bac-
teria (Robicsek et al. 2006; Strahilevitz et al.
2009).
Aminoglycoside Phosphotransferases
The second largest group of AMEs is the APHs.
This structurally diverse group of enzymes acts
like kinases in that they catalyze the ATP-depen-
dent phosphorylation of hydroxyl groups found
on aminoglycosides (Fig. 3B). APH enzymes
are functionally and structurally similar to the
serine–threonine and tyrosine kinases found in
eukaryotes (Wright and Thompson 1999). The
modifications made by these enzymes lower
binding affinity to the target by decreasing the
hydrogen bonding potential of aminoglycoside
hydroxyl groups with important rRNA residues.
Most of the .30 described APH enzymes
belong to the APH(30) subfamily (Kim and
Mobashery 2005), although variants that target
the 200 hydroxyl also exist (Ramirez and Tolma-
sky 2010). These enzymes are found in diverse
groups of Gram-negative bacteria, although
APH(30)-IIIa was discovered in S. aureus and
Enterococcus spp. All members of the family
lead to kanamycin and neomycin resistance
with various members of the family also able
to modify a variety of other aminoglycosides,
including amikacin and gentamicin B (Shaw
et al. 1993).
Aminoglycoside Nucleotidyltransferases
The final group of AMEs is the ANTs. These en-
zymes act by adding AMP from an ATP donor
to hydroxyl groups at the 200,3
00,4
0, 6, and 9
positions (Fig. 3C). The most clinically relevant
members of the class include ANT(200 ) and
ANT(40) (Kotra et al. 2000; Magnet and Blan-
chard 2005), which were first described in
K. pneumoniae and S. aureus, respectively (Ben-
veniste and Davies 1971; Le Goffic et al. 1976).
ANT(200) broadly effects the activity of 4,6-
di-substituted aminoglycosides (Gates 1988),
whereas ANT(40) targets kanamycin A, B, and
C, gentamicin A, amikacin, tobramycin, and
neomycin B and C. Other members of this class
include ANT(300), ANT(6), and ANT(9), which
confer resistance to streptomycin and spectino-
mycin (Hollingshead and Vapnek 1985; Mur-
phy 1985; Ounissi et al. 1990).
16S rRNA Methylation
Target site modification leading to aminogly-
coside resistance occurs via the action of 16S
rRNA methyltransferases (RMTs). These en-
zymes modify specific rRNA nucleotide resi-
dues in a manner that blocks aminoglycosides
from effectively binding to their target (Beau-
clerk and Cundliffe 1987; Cundliffe 1989; Wa-
chino and Arakawa 2012). There are two general
classes of RMTs that are characterized by the
specific nucleotide residues that they modify.
These include enzymes that render bacteria
resistant to 4,6-di-substituted aminoglycosides
via methylation of the N7 position of nucleo-
tide G
1405
(Thompson et al. 1985; Beauclerk
and Cundliffe 1987) and those that affect both
4,6- and 4,5-di-substituted aminoglycosides
through methylation of the N1 position of nu-
cleotide A
1408
(Skeggs et al. 1985; Beauclerk and
Cundliffe 1987; Mingeot-Leclercq et al. 1999).
The first clinical case of a pathogen with
an RMT as a mechanis m of aminoglycoside re-
sistance was reported in a P. aeruginosa isolate
from Japan in 2003 (Yokoyama et al. 2003). This
isolate contained a plasmid-encoded RMT,
named RmtA for ribosomal methyltransferase
A. Subsequently, several additional plasmid-
borne RMTs, encoded by the genes armA,
rmtB1, rmtB2,rmtC,rmtD,rmtD2,rmtE,
rmtF,rmtG, and rmtH, have emerged in clinical
isolates that show high-level resistance to mul-
tiple aminoglycosides (Yokoyama et al. 2003;
Doi et al. 2004; Yan et al. 2004; Yamane et al.
2005; Wachino et al. 2006; Wachino and Ara-
kawa 2012). These enzymes modify the G
1405
nucleotide and, thus, impact the activity of all
4,6-di-substituted aminoglycosides (i.e., ami-
kacin, gentamicin, and tobramycin). In 2007,
Aminoglycosides: An Overview
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the enzyme NpmAwas discovered encoded on a
plasmid in an aminoglycoside-resistant E. coli
clinical isolate, also from Japan (Wachino et al.
2007). This methyltransferase modifies the
A
1408
nucleotide and, thus, impacts 4,6- and
4,5-di-substituted as well as monosubstituted
aminoglycosides, conferring pan-aminoglyco-
side resistance. To date, there has been only
one additional report of this enzyme in a clinical
isolate (Al Sheikh et al. 2014).
Efflux-Mediated Resistance
Several members of the resistance– nodula-
tion–division (RND) family of efflux systems
have been shown to be involved in intrinsic ami-
noglycoside resistance in various pathogens
(Aires et al. 1999; Westbrock-Wadman et al.
1999; Rosenberg et al. 2000; Magnet et al. 2001;
Hocquet et al. 2003; Islam et al. 2004). In the
opportunistic pathogen P. aeruginosa, intrinsic
low-level resistance to aminoglycosides, tetracy-
cline and erythromycin, is mediated by the ex-
pression of the multiple efflux (Mex) XY-OprM
system. MexXY orthologs are found in other
species of bacteria. For example, members of
the Burkholderia cenopacia complex are often
intrinsically resistant to aminoglycosides via
RND efflux pumps (Buroni et al. 2009). A ho-
mologous transporter in E. coli, AcrD, partici-
pates in efflux of aminoglycosides (Rosenberg
et al. 2000) as does the Acinetobacter drug efflux
(Ade) ABC efflux system in A. baumannii
(Magnet et al. 2001) and the major facilitator
superfamily (MFS) in Mycobacteria spp.
Molecular Epidemiology of Aminoglycoside
Resistance Mechanisms
Comprehensive molecular data regarding the
current prevalence of specific aminoglycoside
resistance mechanisms among common patho-
gens is sparse. One recent study evaluated the
aminoglycoside resistance mechanisms found
among 200 Gram-negative bacilli isolates se-
lected at random from an extensive culture col-
lection (Castanheira et al. 2015). Ninety-nine
Enterobacteriaceae (91.9% AME-positive), 49
A. baumannii (79.6% AME-positive), and 52
P. aeruginosa (63.5% AME positive) with a va-
riety of aminoglycoside resistance profiles were
included. A diversity of AME genes were iden-
tified with the most prevalent being aac(60)-Ib
(n¼75), ant(30)-Ia (n¼51), and aac(3)-IIa
(n¼45), and with 26 isolates harboring more
than one AME gene. In addition, 21 of the iso-
lates were found to carry an RMT including
12 Enterobacteriaceae, seven A. baumannii, and
two P. aeruginosa. Many of these isolates were
also resistant to other common antibiotics used
to treat Gram-negative infections, highlight-
ing the ability of these resistance mechanisms
to spread through conjugation of plasmids and
nonreplicative transposons among bacteria
(Courvalin 1994; Waters 1999; Dzidic and Be-
dekovic
´2003; Feizabadi et al. 2004).
AMEs are commonly found in association
with other key resistance elements, such as
carbapenemases and extended spectrum b-lac-
tamases (ESBLs). Among 50 carbapenem-resis-
tant K. pneumoniae clinical isolates from two
U.S. medical centers (80% possessing KPC-2,
10% possessing KPC-3 with all KPC
þ
isolates
also expressing TEM-1 and SHV-12), 98% of
isolates expressed at least one AME (Alma-
ghrabi et al. 2014). Specifically, 98% were pos-
itive for aac(60)-Ib, 56% positive for aph(30)-Ia,
38% positive for aac(30)-IV, and 2% positive for
ant(200)-Ia. Overall, 40%, 98%, and 16% of the
strains were nonsusceptible to gentamicin, to-
bramycin, and amikacin, respectively. Plazomi-
cin, a novel aminoglycoside in clinical develop-
ment that was designed to evade AME-based
resistance, had MICs that ranged from 0.25
to 1 mg/mL against this set of isolates. AME
characterization in 330 aminoglycoside-resis-
tant clinical Enterobacteriaceae isolates from
Spain revealed the presence of aph(300)-Ib and
ant(300)-Ia genes in 65.4% and 37.5% of the
isolates, consistent with 92% phenotypic resis-
tance to streptomycin found in this strain col-
lection (Miro
´et al. 2013). These isolates were
resistant to other aminoglycosides to varying
degrees, including gentamicin (18.4%), tobra-
mycin (16.9%), and amikacin (1.5%), indicat-
ing the presence of other AMEs; aph(30)-Ia was
found in 13.9% of isolates, aac(3)-IIa in 12.4%,
aac(60)-Ib in 4.2%, ant(200)-Ia in 3.6%, and
K.M. Krause et al.
8Cite this article as Cold Spring Harb Perspect Med 2016;6:a027029
www.perspectivesinmedicine.org
aph(300 )-IIa 1.2% (Miro
´et al. 2013). Under-
scoring the association of AMEs with resistance
elements to other key antibiotic classes, many of
these isolates also produced ESBLs and were
resistant to the fluoroquinolones.
Similar to the AMEs, comprehensive data
describing the prevalence and molecular epide-
miology of RMTs is lacking. A recent literature
review described reports of widespread, global
dissemination of genes encoding RMTs among
isolates from both human and livestock sources
(Wachino and Arakawa 2012). Despite the
widespread detection of RMTs across many re-
gions, the prevalence appears to vary by region
with the highest rates reported in Asia. A
SENTRY surveillance study from the Asia-Pa-
cific region (2007–2008) detected genes encod-
ing RMTs in 6.9% (China), 10.5% (India), 1.5%
(Hong Kong), 6.1% (Korea), and 5.0% (Tai-
wan) of Enterobacteriaceae isolates (Bell et al.
2010). Lower rates (1.3%) of RMTs among
Enterobacteriaceae have been reported from
single institution or local studies from Euro-
pean medical centers (Wachino and Arakawa
2012). Similar to the association between
AMEs and other key resistance mechanisms,
an association between RMTs and specific
b-lactamases has been described. Seventy-six
percent of the RMT containing isolates de-
scribed in the SENTRY surveillance study above
also possessed a CTX-M ESBL (Bell et al. 2010),
and RMTs are frequently found in associa-
tion with the New Delhi metallo-b-lactamase
(NDM) (Berc¸ot et al. 2011; Livermore et al.
2011; Mushtaq et al. 2011; Poirel et al. 2014).
AGENTS IN DEVELOPMENT
Plazomicin is a new aminoglycoside that was
specifically engineered to be resistant to the ac-
tion of the AMEs that are prevalent in key
Gram-negative pathogens (Armstrong and Mil-
ler 2010). It is synthesized from a sisomicin
scaffold that is intrinsically refractory to mod-
ification by APH(30)-III, -VI, and -VII and
ANT(40), which confer amikacin resistance be-
cause of an absence of the 30- and 40-OH groups.
Modification at the N-1 position via addition
of a hydroxylaminobutyric acid substituent
sterically hinders the action of the AAC(3),
ANT(200), and APH(200 ) enzymes, which confer
resistance to gentamicin and tobramycin. Final-
ly, addition of a hydroxyethyl substituent at the
60position inhibits the action of the AAC(60)
enzymes, which confer resistance to a broad
range of agents, including amikacin, tobramy-
cin, and gentamicin (Fig. 4). Importantly, these
modifications to sisomicin do not reduce in-
trinsic potency as has been associated with pre-
vious efforts to protect the 60position and,
as predicted, lead to improved activity against
Enterobacteriaceae (MIC
90
2mg/L) that are
resistant to currently available aminoglycosides
(Nagabhushan et al. 1982; Aggen et al. 2010).
Plazomicin retains vulnerability to modifica-
tion by AAC(20)-I, a chromosomal AME found
in P. stuartii and some mycobacterial species.
However, this enzyme is rare, has not been
found on a mobile element and has not been
shown to have clinical relevance in Mycobac-
terium spp. In addition, plazomicin, like all
Arbekacin
Plazomicin
O
O
HN
O
O
OH
HO
O
HO
NH
OH
OH
HN H2N
NH2
NH2
O
OO
O
OH
O
OH
OH
OH
HO
H2N
H2N
H2N
NH2
NH
NH2
Figure 4. Structures of plazomicin and arbekacin.
Aminoglycosides: An Overview
Cite this article as Cold Spring Harb Perspect Med 2016;6:a027029 9
www.perspectivesinmedicine.org
4,6-linked aminoglycosides, is inactive against
isolates that produce RMTs. As described
above, this mechanism of resistance frequently
travels on mobile genetic elements with NDM-
positive Enterobacteriaceae, and, thus, plazo-
micin is not active against many isolates har-
boring this enzyme (Berc¸ot et al. 2011; Liver-
more et al. 2011; Mushtaq et al. 2011; Poirel
et al. 2014).
Similar to plazomicin, arbekacin, a semi-
synthetic derivative of dibekacin, was specifi-
cally engineered to overcome the action of
a subset of clinically important AMEs (Fig.
4). Arbekacin is stable to the action of
AMEs commonly found in methicillin-resis-
tant S. aureus (MRSA), such as APH, ANT,
and AAC and possesses potent activity against
this clinically important pathogen (Matsu-
moto 2014). Although arbekacin has been
approved for use in Japan since 1990 for the
treatment of sepsis and pneumonia caused
by MRSA, this molecule also retains potent
activity against key Gram-negative pathogens,
including MDR strains, and has more recently
gained attention as a potential therapy for in-
fections caused by these organisms.In a recent
surveillance study of isolates from hospitalized
patients with pneumonia, arbekacin was the
most potent aminoglycoside tested against
ESBL-producing E. coli and was slightly more
active than amikacin and tobramycin against
ESBL- and KPC-expressing K. pneumoniae.
Similarly, arbekacin possessed greater activity
against P. aeruginosa and Acinetobacter spp.,
including MDR isolates, than the other ami-
noglycosides tested (amikacin, gentamicin,
and tobramcin) (Sader et al. 2015). Because
of its broad-spectrum in vitro activity against
both MDR Gram-positive and Gram-negative
pathogens, arbekacin is currently under de-
velopment as an inhalational agent for the
treatment of mechanically ventilated patients
with bacterial pneumonia (clinicaltrials.gov/
ct2/show/NCT02459158) and is under study
at Walter Reed Army Medical Hospital for
the treatment of patients with infections caused
by MDR organisms that have limited treat-
ment options (clinicaltrials.gov/ct2/show/
NCT01659515).
PHARMACOKINETICS AND
PHARMACODYNAMICS
Aminoglycosides are poorly absorbed via the
gastrointestinal (GI) tract and are, thus, admin-
istered via the intravenous or intramuscular
route (Ramirez and Tolmasky 2010; Craig
2011). The volume of distribution for members
of the aminoglycoside class approaches total
body volume, indicating a broad distribution
into tissues, including the lung (Simon et al.
1973). This feature has led to extensive use
of aminoglycosides as part of combination
regimens for the treatment of pneumonia. Ami-
noglycosides are rapidly cleared through the
urinary tract, which also makes these drugs ide-
al for the treatment of urinary tract infections
(Lode et al. 1976; Ramirez and Tolmasky 2010;
Craig 2011).
The relationship between aminoglycoside
pharmacokinetics (PKs) and pharmacodynam-
ics (PDs) has been studied extensively in mice.
The PK/PD variable that is most often correlat-
ed with efficacy of aminoglycosides is the ratio
of area under the concentration– time curve
(AUC) to MIC, although peak concentration
also appears to play a role. The magnitude of
the PK/PD target for aminoglycosides is not as
well defined as it is for other antibiotic classes
because of, until recently, the lack of develop-
ment of new aminoglycosides. Available data
suggests that significant variations in the PK/
PD target exist between species and body site
of infection. For example, an AUC/MIC target
of 100 was reportedly associated with a 1- to 2-
log
10
kill in the mouse neutropenic thigh infec-
tion model with amikacin and K. pneumoniae
(Craig 2011), whereas this same group reported
better efficacy at the same dose level and w ith the
same strain in the mouse lung infection model
(Craig et al. 1991). These results were potentially
a result of a longer measured PAE in the lung
compared with the thigh (Craig et al. 1991).
AUC /MIC thresholds have been correlated
to efficacy in patients in whom extensive PK
sampling was also conducted. These case re-
ports and reviews describe a variety of different
ways that the AUC/MIC ratio might be used to
predict outcomes in patients. Smith et al. (2001)
K.M. Krause et al.
10 Cite this article as Cold Spring Harb Perspect Med 2016;6:a027029
www.perspectivesinmedicine.org
reviewed 23 patients with intra-abdominal in-
fections (n¼16) or lower respiratory infec-
tions (n¼7) treated with tobramycin infused
.30 min to achieve a C
max
of between 4 and
10 mg/L. A PK/PD model constructed from
these patients data showed that improved effi-
cacy was observed when an AUC/MIC ratio of
110 was achieved compared with AUC/MIC
ratios of ,110 (80% clinical cure rate compared
with 47%). Other investigators have found sim-
ilar correlations between exposure and efficacy.
Jacobs (2001) describes the need to achieve an
AUC /MIC ratio of 25 for less severe infections
or in immune competent patients and a ratio of
at least 100 in patients with severe infections
and/or those that are immune-compromised.
Zelenitsky et al. (2003) found significantly im-
proved outcomes in patients with bacteremia
treated with gentamicin when AUC/MIC ratios
exceeded 70 compared with AUC/MIC ratios
,70 (90% cure vs. 45.5%, respectively). How-
ever, a much stronger correlation with outcome
was noted for C
max
/MIC with 84% and 90%
clinical cure rates for C
max
/MIC values of 4.8 or
8 compared with 0% clinical cure for C
max
/
MIC ,2.9.
There is substantial evidence that adminis-
tering larger doses of aminoglycosides less fre-
quently may be associated with improved out-
comes compared with providing the same total
daily dose over more frequent dosing schedules
(Barclay et al. 1999). This dosing approach,
known as once daily or extended interval dos-
ing, takes advantage of three features of amino-
glycosides—concentration-dependent killing,
rapid elimination, and a prolonged PAE. Larger
doses are thought to increase target body site
concentrations to improve PD while minimiz-
ing potential toxicity through allowance for a
period of time in which there is little or no
drug in circulation. The PAE properties of the
class allow for an extended period of killing after
the drug is cleared from the body and before the
next dose is administered. A number of meta-
analyses of results from clinical trials comparing
once versus multiple daily administration of
aminoglycosides have been published (Barclay
et al. 1999). Overall, the results of these studies
suggest that once daily dosing is associated with
reduced nephrotoxicity and equal, if not slightly
improved, efficacy.
Therapeutic drug management (TDM), the
clinical practice of measuring drug concentra-
tions at designated intervals for use in optimiz-
ing individualized dosage regimens, has further
improved the safety profile of aminoglycosides.
Older studies using multiple daily doses of these
drugs have shown nephrotoxicity rates of 10%
to 20% (Humes et al. 1982; Moore et al. 1984),
whereas lower rates of nephrotoxicity ranging
from 0% to 14% have been reported with
once-daily dosing regimens with dose adjust-
ment guided by the use of TDM (Prins et al.
1993; Nicolau et al. 1995; Murry et al. 1999;
Rybak et al. 1999; Buijk et al. 2002). The advan-
tages of once-daily or extended interval dosing
of aminoglycosides combined with the use of
TDM are now widely accepted and, for many
infection types, this dosing approach has be-
come the standard of care (Avent et al. 2011).
CLINICAL USES OF AMINOGLYCOSIDES
The spectrum of activity, rapid bactericidal ac-
tivity, and favorable chemical and pharmacoki-
netic properties of aminoglycosides make them
a clinically useful class of drugs. Aminoglyco-
sides are used as single agents and in combina-
tion with other antibiotics in both empirical
and definitive therapy for a broad range of in-
dications (Avent et al. 2011; Jackson et al. 2013).
In patients with serious infections caused
by Gram-negative pathogens, the receipt of em-
piric combination therapy containing at least
one antimicrobial agent to which the pathogen
is susceptible leads to lower mortality and
improved outcomes (Tamma et al. 2012). In ad-
dition to helping ensure that the pathogen is
adequately covered by at least one active drug,
the use of empiric aminoglycoside-b-lactam
combination therapy has also been theorized
to contribute to improved outcomes by taking
advantage of the in vitro synergy observed be-
tween these classes and to prevent the emergence
of resistance (Pankuch et al. 2010; Le et al. 2011).
Although clinical data to support the latter two
theoretical benefits of combination therapy are
conflicting (Tamma et al. 2012), aminoglyco-
Aminoglycosides: An Overview
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www.perspectivesinmedicine.org
sides are often combined with b-lactams for the
empirical treatment of severe sepsis and certain
nosocomial infections in patients with a high
risk of mortality or when there is concern that
the causative pathogen may be resistant to more
commonly used agents (American Thoracic
Society; Infectious Diseases Society of America
2005; Dellinger et al. 2013). More recently, ami-
noglycosides have increasingly become impor-
tant components of therapy for patients infected
with MDR pathogens, such as carbapenem-
resistant Enterobacteriaceae (CRE), for whom
few treatment options remain. In a retrospective
cohort study of 50 cases of sepsis caused by car-
bapenem- and colistin-resistant K. pneumoniae,
the receipt of gentamicin as part of definitive
therapy was associated with lower mortality
compared with the receipt of non-gentamicin-
containing regimens (Gonzalez-Padilla et al.
2015). The novel aminoglycoside plazomicin
(see section on Agents in Development) is cur-
rently under phase 3 study for the treatment of
serious infections caused by CRE (clinicaltrials
.gov/ct2/show/NCT01970371).
Aminoglycosides are also an important
component of combination therapy for multi-
drug-resistant tuberculosis (MDR-TB) and cer-
tain non-tuberculous mycobacterial (NTM)
infections. Current MDR-TB treatment guide-
lines recommend inclusion of one of the follow-
ing agents during the intensive phase of therapy:
amikacin, kanamycin, streptomycin, or capreo-
mycin, a cyclic peptide antibiotic that is often
considered as an aminoglycoside because of
its mechanism of action. Each of these agents
possesses potent bactericidal activity against
M. tuberculosis (Ho et al. 1997) and the choice
of agent depends on previous injectable use (if
any) and the likelihood of resistance. A meta-
analysis including 32 studies with .9000 treat-
ment episodes did not reveal any clear differenc-
es in efficacy among the available agents (World
Health Organization 2011). Similar to treat-
ment of MDR-TB, combination therapy for
patients with fibrocavitary, severe nodular/
bronchiectatic or macrolide-resistant lung dis-
ease because of the M. avium complex general-
ly includes amikacin or streptomycin (Griffith
et al. 2007). Among the rapidly growing myco-
bacteria, amikacin is the preferred agent for in-
fections because of M. fortuitum or M. abscessus,
whereas tobramycin is the most active agent
against M. chelonae (Griffith et al. 2007).
Aminoglycosides remain the preferred
therapy for certain zoonotic infections such as
plague and tularemia. Although streptomycin
has traditionally been the agent of choice for
these infection types, gentamicin is now widely
used because of the broader availability of this
agent as well as data suggesting similar efficacy
to streptomycin (Mwengee et al. 2006; Snowden
and Stovall 2011). Aminoglycosides are bacter-
icidal against these organisms and the use of
bacteriostatic agents, such as doxycycline or
chloramphenicol has led to treatment failures
(Dennis et al. 2001; Snowden and Stovall 2011).
Inhaled tobramycin therapy in CF patients
with chronic lung infection caused by P. aerugi-
nosa has been shown to improve respiratory
function, decrease hospitalizations, and reduce
systemic antibiotic use (Ramseyet al. 1999), and
has contributed to a significant increase in sur-
vival for these patients (Sawicki et al. 2012).
Inhaled aminoglycosides, alone or as part of
combination therapy, are currently under eval-
uation as adjunctive agents for treatment of ad-
ditional respiratory infection types including
chronic lung infections associated with non-
CF bronchiectasis and refractory NTM infec-
tions of the lung, and for the prevention and/
or treatment of ventilator associated infec-
tions, tracheobronchitis (VAT), and pneumonia
(VAP). Regarding the latter indication, although
definitive data from large randomized trials is
not available, a number of small studies focused
on the prevention or treatment of VAP have
provided encouraging results. A meta-analysis
of eight comparative trials of prophylactic aero-
solized antibiotics (four of which used inhaled
tobramycin or gentamicin) found that ICU-ac-
quired pneumonia was less common in the
group of patients that received antibiotic pro-
phylaxis compared with those who received no
prophylaxis (Falagas et al. 2006). Similarly, a
meta-analysis of five comparative trials of ad-
junctive aerosolized antibiotics in the treatment
of VAP, each of which evaluated an inhaled ami-
noglycoside versus placebo or no therapy, re-
K.M. Krause et al.
12 Cite this article as Cold Spring Harb Perspect Med 2016;6:a027029
www.perspectivesinmedicine.org
vealed that administration of aerosolized anti-
biotics was associated with better treatment
success compared with control in both the
intent-to-treat and clinically evaluable popula-
tions (Ioannidou et al. 2007). The relative inef-
ficiency of drug delivery through the ventilator
circuit is a significant challenge with the use of
aerosolized antibiotics for the treatment of ven-
tilator-associated infections. To overcome this
issue, BAY41-6551, an investigational drug– de-
vice combination of amikacin specifically for-
mulated for inhalation, has been developed.
This drug–device combination is currently
under phase 3 study as adjunctive therapy in
intubated and mechanically ventilated patients
with Gram-negative pneumonia (clinicaltrials
.gov/ct2/show/NCT01799993 and clinicaltrials
.gov/ct2/show/results/NCT00805168).
Because of their poor oral bioavailability,
aminoglycosides are a key element of oropha-
ryngeal or gut decolonization/decontamina-
tion regimens, including those targeting MDR
pathogens. The purpose of these decontamina-
tion regimens is to eradicate potential pathogens
from the oropharynx and digestive tract of pa-
tients at risk for nosocomial or postoperative
infections. Selective digestive decontamination
(SDD) consists of the oropharyngeal and gastric
administration of non-absorbable antibiotics
lacking anaerobic activity (often a polymyxin,
an aminoglycoside, and amphotericin) along
with a short course of systemic antibiotic thera-
py, whereas selective oropharyngeal decon-
tamination (SOD) consists of application of
non-absorbable antibiotics to the oropharynx
alone. More than 50 randomized studies and
10 meta-analyses of SDD/SOD have been pub-
lished. Overall, these data suggest that SDD/
SOD are associated with improved survival in
ICU patients (Price et al. 2014) and SDD is as-
sociated with a reduction in the rate of post-
operative infection, including anastomotic leak-
age, in patients undergoing elective GI surgery
(Abis et al. 2013; Roos et al. 2013). Despite these
successes in the use of SOD and SDD to improve
patient outcomes in the setting of low levels
of antibiotic resistance, controversy remains re-
garding their effectiveness in the setting of high
levels of antibiotic resistance as well as their im-
pact on antibiotic resistance. No relationship
between the use of SDD or SOD and the devel-
opment of antimicrobial resistance has been
shown in individual studies or meta-analyses
in the setting of low antibiotic resistance (Dane-
man et al. 2013; Plantinga and Bonten 2015)
and an international multicenter study of the
effects of SDD and SOD on ICU-level antibiotic
resistance in countries with higher levels of re-
sistance is currently ongoing (clinicaltrials.gov/
ct2/show/NCT02208154).
The ability of paromomycin to bind to eu-
karyotic ribosomes has led to the use of this
agent in the treatment of protozoal infections.
Like other aminoglycosides, oral paromomycin
is poorly absorbed and may be used for the
treatment of noninvasive amebiasis, crypto-
sporidiosis, trichomoniasis, and giardiasis in
patients in whom other agents are contraindi-
cated (Stover et al. 2012). More recently, this
agent has been used to treat both cutaneous
and visceral leishmaniasis. Topical paromomy-
cin yielded a significantly higher cure rate com-
pared with control therapy in patients with
cutaneous leishmaniasis caused by Leishmania
major (Ben Salah et al. 2013). Intramuscular
paromomycin monotherapy was noninferior
to standard amphotericin B therapy in a ran-
domized control trial in patients with visceral
disease in India (Sundar et al. 2007) and short-
course combination regimens containing this
agent were also noninferior to standard therapy
with fewer adverse events (Sundar et al. 2011).
CONCLUSIONS
The aminoglycosides are a critical component
of the current antibacterial arsenal. Their broad
spectrum of activity, rapid bactericidal action,
and favorable chemical and pharmacokinetic
properties make them a clinically useful class
of drugs across numerous infection types, in-
cluding certain protozoal infections. The use
of aminoglycosides waned as a result of the
emergence of other classes of broad-spectrum
agents with improved safety profiles, but the
emergence of MDR pathogens has led to re-
newed interest in this class of drugs. Improved
understanding of the drivers of toxicity and
Aminoglycosides: An Overview
Cite this article as Cold Spring Harb Perspect Med 2016;6:a027029 13
www.perspectivesinmedicine.org
efficacy has led to the implementation of opti-
mized dosing regimens that improve safety
while maintaining efficacy. Increased under-
standing of key aminoglycoside resistance
mechanisms combined with innovative me-
dicinal chemistry approaches have led to the
synthesis and development of novel agents
specifically designed to evade resistance while
maintaining potency against fully susceptible
isolates. Given the dearth of new agents in the
antibiotic pipeline and the ever-increasing spec-
ter of resistance, further optimization of the
aminoglycoside scaffold to generate new agents
with superior potency against MDR pathogens
as well as an improved safety profile is warranted.
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