Structure-based design, synthesis and A-site rRNA co-crystal complexes of novel amphiphilic aminoglycoside antibiotics with new binding modes: A synergistic hydrophobic effect against resistant bacteria

Article abstract of DOI:10.1016/j.bmcl.2010.09.084

Incorporation of an hydrophobic (phenethylamino)ethyl ether at C2″ of N1-(HABA)-3′,4′-dideoxyparomomycin led to a novel analog with an excellent antibacterial profile against a host of resistant bacteria.

Full text of DOI:10.1016/j.bmcl.2010.09.084

Bioorganic & Medicinal Chemistry Letters 20 (2010) 7097–7101
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Structure-based design, synthesis and A-site rRNA co-crystal complexes
of novel amphiphilic aminoglycoside antibiotics with new binding modes:
A synergistic hydrophobic effect against resistant bacteria
Stephen Hanessian a, , Kandasamy Pachamuthu a, Janek Szychowski a, Alexandre Giguère a, Eric E. Swayze b,
⇑
Michael T. Migawa b, Boris François c, Jiro Kondo c,d, Eric Westhof c
a Department of Chemistry, Université de Montréal, C. P. 6128, Succ. Centre-Ville, Montréal, P. Q., Canada H3C 3J7
b Isis Pharmaceuticals, 2292 Faraday Drive, Carlsbad, CA 92008, USA
c Architecture et réactivité de l’ARN, IBMC-CNRS, Université de Strasbourg, 15 rue René Descartes, 67084 Strasbourg Cedex, France
d Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioi-cho, Chiyoda-ku, Tokyo 102-8554, Japan
a r t i c l e i n f o
a b s t r a c t
Incorporation of an hydrophobic (phenethylamino)ethyl ether at C200 of N1-(HABA)-30,40-dideoxyparomo-
mycin led to a novel analog with an excellent antibacterial profile against a host of resistant bacteria.
Ó 2010 Elsevier Ltd. All rights reserved.
Article history:
Received 4 August 2010
Accepted 14 September 2010
Available online 19 September 2010
Keywords:
Antibiotic resistance
Aminoglycoside
RNA-complex
Introduction
of aminoglycosides such as kanamycin (9) with the objective of
expanding its antibacterial activity to include a larger panel of
The inevitable development of acquired resistance to antibiotic
substances through a variety of mechanisms has been a challeng-
ing obstacle in long term human therapy.1 Over time, bacteria
are able to become resistant to the action of antibiotics, mainly
through mutation, enzymatic attack at critical sites and reduced
permeability. In spite of their potent activity as bactericidal com-
pounds, the widespread use of aminoglycosides as chemothera-
peutic agents has been curtailed by the development of
resistance.2 Thus, the well known naturally occurring aminoglyco-
sides in the 4,5 and 4,6-disubstituted 2-deoxystreptamine series,
such as paromomycin (1) (Fig. 1) or neomycin (2) and kanamycin
(9) respectively are not first choice therapies, in spite of their excel-
lent antibacterial activities in vitro against a variety of Gram-posi-
tive and Gram-negative microorganisms. Two of the more
successful aminoglycosides, namely the gentamicin C complex
(8) and tobramycin (10) on the other hand, are used as intravenous
and inhaler formulations, respectively.3 A key structural feature in
these naturally occurring antibiotics is the absence of a C30 and/or
C40 hydroxyl groups which are sites for enzymatic deactivation by
O-phosphotransferases and O-nucleotidyltransferases.4 With this
knowledge, much effort was devoted to the chemical modification
resistant bacteria. These efforts culminated with the synthesis of
30,40-dideoxykanamycin and related aminoglycosides with promis-
ing antibacterial profiles.5 In this context, it should be mentioned
that Nature has also been a guiding force with the discovery of
butirosin (6), a 4,5-disubsituted 2-deoxystreptamine pseudo-tri-
saccharide containing the N1-(2S)-2-hydroxy-4-aminobutyric
amide (HABA) moiety, although its further development was not
pursued.6
A major breakthrough came with the development of amikacin
(11), a derivative of kanamycin in which the N1 amino group of
deoxystreptamine was acylated with a HABA side-chain.7 Indeed,
amikacin was found to exhibit activity against certain non-resis-
tant strains of Pseudomonas aeruginosa. A logical extension toward
more effective clinical candidates was the development of arbeka-
cin (12),8 in which the beneficial effects of the 30,40-dideoxy ring I
and the N1-HABA moiety were combined. No new aminoglycoside-
type antibiotic has been introduced in the market during the past
two decades. The mode of action of aminoglycosides as inhibitors
of protein biosynthesis at the ribosomal level has been extensively
studied. Seminal contributions have recently provided insights into
the structure of the ribosome, and binding sites of aminoglycoside
antibiotics at the A site of the 30S subunit.9 These studies have
instigated a renewed interest in the chemistry of aminoglycosides.
A large number of chemically modified analogs has been reported
⇑
Corresponding author.
E-mail address: stephen.hanessian@umontreal.ca (S. Hanessian).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.09.084

7098
S. Hanessian et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7097–7101
R3HN
HO
H2N
Me
NH2
O
OH
H
R1
R2
NH2
O
O
NHMe
II
MeHN
Me
O
4'
O
I
OH
HO
O
O
R4O
3'
OH
2'I' II
H2N
R2
O
H2N
H2N
O
IV
O
gentamicin complex (C1 shown) (8)
NH2
HO
(S)-2-hydroxy-4-aminobutyric
acid or amide (HABA)
OH
O
R4HN
OH
HO
NH2
NH2
R1
O
NH2
O
H2N
HO
R1 = OH, R2 = OH, R3 = H, R4 = H, paromomycin (1)
R1 = NH2, R2 = OH, R3 = H, R4 = H, neomycin B (2)
R1 = OH, R2 = H, R3 = H, R4 = H (3)
O
O
HO
R3
R2
OH
R1, R2 = OH, R3 = OH, R4 =H, kanamycin A (9)
R1 = OH, R2 = OH, R3= HABA, R4 = H (4)
R1 = OH, R2 = H, R3 = NH2, R4 = H, tobramycin (10)
R1, R2 = OH, R3 = OH, R4 = HABA, amikacin (11)
R1, R2 = H, R3 = NH2 R4 = HABA, arbekacin (12)
R1 = NH2, R2 = OH, R3 = HABA, R4 = H (5)
R1 = NH2, R2 = OH, R3 = HABA, Ring IV= H, butirosin (6)
R1 = OH, R2 = OH, R3 = H, R4 = (CH2)2N(CH2)2Ph (7)
Figure 1. Representative members of the aminoglycoside family.
with promising results, although few new insights were gained
with regard to improved antibacterial profiles or diminished enzy-
matic resistance.
silylation to the penta-O-TBS ether. Cleavage of the carbamate,
introduction of the HABA group, followed by ozonolysis of the
allylic double bond, reductive amination and global deprotection
led to the analog 15.
In a previous letter, we revealed a new paradigm in the design
and synthesis of functionally diverse analogs of paromomycin.10 It
was found that placing hydrophobic end-groups on aminoethyl al-
kyl ethers at the C200 hydroxyl group in the b-ribofuranosyl (ring III)
unit of paromomycin, as in 7, maintained the antibacterial activity
in a panel of bacterial strains. Furthermore, X-ray crystal structures
of complexes of some analogs with an A-site RNA model fragment
revealed a new mode of binding for rings III and IV. While the pre-
cise reasons for in vitro antibacterial activity of such a modified
analog of paromomycin cannot be delineated at this time, it is clear
that the incorporation of a C200 ether chain with a hydrophobic or a
heteroaromatic end-group has a potentially beneficial effect. Based
on these promising results,10,11 and interesting X-ray structural
data, we focused our attention on exploiting this new paradigm
with other analogs in conjunction with the presence of an N1-
HABA moiety. Such HABA derivatives of paromomycin 4 and
neomycin 5 were reported in the literature, along with the 30,40-
dideoxygenated version of paromomycin several years ago.12,13
We decided to combine these features into new analogs of paro-
momycin. Guided by preliminary antibacterial testing,14 we also
incorporated the preferred 200-(phenethylamino)ethyl ether in se-
lected derivatives. These studies have led to a potent new analog
with unprecedented in vitro activities against a panel of resistant
bacteria in the paromomycin series. Our design paradigm was also
substantiated by X-ray co-crystal structures of these modified ana-
logs with the A-site rRNA fragment.
We then proceeded with the synthesis of a ring A-modified ana-
log (Scheme 2). The known intermediate 16,13 was O-silylated,
then subjected to a regioselective O-allylation to give 17. At this
juncture, it was necessary to protect the remaining hydroxyl
groups as benzoate esters. Oxidative cleavage of the allylic double
bond, followed by a reductive amination with phenethylamine,
then global deprotection, gave 200-O-(phenethylamino)ethyl 30,40-
dideoxy paromomycin (18).
We concluded this series with the synthesis of an analog that
contained the N1-HABA moiety and the 200-O-(phenethylami-
no)ethyl ether groups within the framework of 30,40-dideoxy paro-
momycin (Scheme 3). The known intermediate 16,13 was treated
with Wilkinson’s catalyst to selectively reduce the double bond
in the presence of the N-Cbz groups. Regioselective O-allylation
at C200 followed by O-silylation and treatment with NaH, led to
the cyclic carbamate which was cleaved to give 19. Introduction
of the HABA side chain followed by ozonolysis, reductive amina-
tion, desilylation and finally hydrogenolysis afforded the analog
20.15
Antibacterial activity
The main objective of this study was to assess the importance, if
any, of combining the N1-HABA paromomycin with a hydrophobic
appendage at C200, known to modify the binding mode of paromo-
mycin to the A-site of the rRNA subunit.10,14 To this end, we se-
lected from compounds with progressive substitution patterns as
shown in Table 1. These were first tested against wild type strains
of Escherichia coli (ATCC#25922) and Staphylococcus aureus
(ATCC#13709) with paromomycin (1) and neomycin (2) as con-
trols. We were not surprised that the incorporation of an N1-HABA
moiety in paromomycin and neomycin did not significantly alter
the intrinsic activities as reflected by MIC values (Table 1, entries
Chemistry
We first addressed the synthesis of an analog of N1-HABA par-
omomycin harboring a hydrophobic ether group at C200 (Scheme 1).
The mono TBS ether was subjected to a chemoselective O-allyla-
tion as previously described to give the key intermediate 13,10,14
and the product was converted to the cyclic carbamate 14 after

S. Hanessian et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7097–7101
7099
O
H2N
H
NH
N
O
CbzHN
HO
O
OH
HO
NHCbz
O
NHCbz
O
OH
OH
O
O
NH2
O
O
O
O
Ph
Ph
O
O
O
O
O
O
O
O
Ph(CH2)2HN
O
O
O
a,b
H2N
OH
c-h
CbzHN
OTBS
O
CbzHN
OH
O
O
H2N
HO
CbzHN
TBSO
OH
OTBS
CbzHN
HO
14
15
13
O
OTBS
O
O
OH NH2
OTBS
NHCbz
OH
NHCbz
Scheme 1. Reagents and conditions: (a) TBSOTf, 2,4,6-collidine, CH2Cl2, 35%; (b) NaH, DMF, 47% (38% SM recovered); (c) LiOH aq, 63% (36% SM recovered); (d) N-Cbz-Haba-
OSu, Et3N, THF, 70%; (e) (i) O3, (ii) PPh3, 67%; (f) RNH2, NaBH3CN, MeOH, AcOH; (g) HF, pyridine, 61% (three steps); (h) AcOH:H2O (4:1), (ii) Pd(OH)2/C, H2, 91%.
CbzHN
HO
O
CbzHN
HO
O
H2N
HO
NHCbz
O
NHCbz
O
OTBS
OH
OH
NH2
O
O
O
O
O
O
O
HO
O
O
Ph(CH2)2HN
a,b
c-f
CbzHN
O
CbzHN
H2N
18
O
O
O
CbzHN
HO
16
CbzHN
HO
H2N
OTBS
17
OH
OH
O
O
O
HO
OH
NHCbz
OH
OH
NHCbz
NH2
Scheme 2. Reagents and conditions: (a) TBSCl, imidazole, CH2Cl2, 68%; (b) allyl iodide, KHMDS, THF, 70%; (c) BzCl, DMAP, pyridine, 82%; (d) O3, (ii) PPh3, 62%; (e) (i)
phenethylamine, NaBH3CN, AcOH, MeOH, (ii) NaOMe, MeOH, 70%; (f) (i) AcOH/H2O (4:1), (ii) Pd(OH)2/C, H2, 92%.
O
H2N
CbzHN
HO
O
H2N
NH
NHCbz
O
NHCbz
O
OH
HO
OH
OTBS
HO
OH
NH2
O
O
O
O
O
O
O
O
O
O
HO
O
O
O
Ph(CH2)2HN
a-e
f-i
CbzHN
CbzHN
O
H2N
20
CbzHN
HO
CbzHN
TBSO
16
H2N
OTBS
19
OH
OH
O
O
O
HO
OH
NHCbz
NH2
OTBSNHCbz
OH
Scheme 3. Reagents and conditions: (a) Wilkinson’s cat., EtOH/THF, 80%; (b) TBSCl, imidazole, CH2Cl2, 70%; (c) allyl iodide, KHMDS, THF, 68%; (d) TBSOTf, 2,4,6-collidine,
CH2Cl2, 77%; (e) NaH, DMF, 49% (26% SM recovered); (f) LiOH aq, 88%; (g) N-Cbz-Haba-OSu, Et3N, THF, 75%; (h) (i) O3, (ii) Me2S; (i) phenethylamine, NaBH3CN, AcOH; (j) HF,
pyridine, 30% (three steps); (k) Pd(OH)2/C, H2, AcOH/H2O (4:1), quant.
(ATCC#25922). One of the outstanding modifications in this series
Table 1
proved to be the known 200-O-(phenethylamino)ethyl paromomy-
Activities of paromomycin and neomycin analogs
cin (7) (Table 1 entry 6). It was interesting to observe that the
Entry
Compounds
MIC E. coli (
l
g/mL)
MIC S. aureus (lg/mL)
activity of N1-HABA 200-O-(phenethylamino)ethyl paromomycin
(15) was significantly improved against E. coli and S. aureus (Table
1, entry 7). Although, a weakening of inhibitory activity was ob-
served with 30,40-dideoxy paromomycin (Table 1, entry 3), it was
expected that introduction of the C200-O-(phenethylamino)ethyl
group as in 18 would restore this loss (Table 1, entry 8). However,
only modest improvement was observed against S. aureus. In con-
trast, the combination of an N1-HABA and 200-O-(phenethylami-
no)ethyl group in the 30,40-dideoxygenated framework of
paromomycin as in 20, produced a potent antibiotic (Table 1, entry
9).
1
2
3
4
5
6
7
8
9
1
2
3
4
5
3–6
3–6
1–2
1–2
5–10
1.3–2.5
2.5–5.0
0.3–0.6
0.6–1.3
1–3
20–40
5–10
2.5–5
3–6
0.6–1.3
40
7
15
18
20
2.5–5.0
0.6–1.3
1–5). In a previous SAR study,14 we had determined that, with few
exceptions, a vast array of modifications at the C200 position were
well tolerated against S. aureus (ATCC#13079). Smaller, aliphatic
and polar functionalities seem to be fare better against E. coli
We have obtained a co-crystal structure of 18 (Fig. 2) with an
A-site RNA model fragment, that shows a similar binding mode
as the one previously reported for 7 and 20.10,11 The C200 ether ana-
log 18 is characterized by the absence of the hydroxyl groups at

7100
S. Hanessian et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7097–7101
Figure 2. X-ray complex of compound (18) with A-site RNA. The U1406°U1495 base pair, the universally conserved A1408 residue, the G1491 residue and two bulged out
adenines, A1492 and A1493, are colored in green, red, cyan, and blue, respectively.
positions 30 and 40 on ring I, as well as the inclusion of a hydropho-
bic ether appendage at C200. The loss of direct contacts to O2P of
A1492 and A1493 was partially compensated by a network of
water molecules bridging N20 of ring I and the anionic phosphate
oxygens. A direct contact between N1 of ring II and O4 of U1495
observed in paromomycin complex was missing, but a new direct
contact between O6 of ring II and O4 of U1406 was observed.15
In the co-crystal with amikacin, the HABA group forms two spe-
cific H-bonds with two stacked alternating G@C pairs beyond the
conserved U°U pair, thereby anchoring firmly the aminoglycoside
on the 30 strand of the A site.16 Although the HABA group does
not improve the affinity, its incorporation together with the
dideoxy modifications on ring I may compensate for the lack of
contacts between the hydroxyl groups at position 30 and 40 of ring
I which occur also on the 30 strand of the model A-site. Thus, the
energetically disfavored dideoxy modifications on ring I, appears
compensated by the contacts of the HABA group two base pairs
away.
Having obtained encouraging results regarding the synergistic
effect of the C200-O-(phenethylamino)ethyl group with an N1-HABA
moiety in paromomycin, we wished to ascertain if this could be ex-
tended to bacteria having acquired resistance against a host of clin-
ically used antibiotics such as vancomycin, oxymycin, levofloxacin,
ciprofloxacin and ceftazidime (Table 2). The inclusion of a 200-O-
(phenethylamino)ethyl group in N1-HABA paromomycin (15) only
modestly improved activity compared to amikacin, ceftazidime or
Table 2
Selected compounds against a panel of resistant bacteria
Organism* (IDa)
ceft. or linz.d
(lg/ml)
4 (lg/mL)
8 (lg/mL)
11 (lg/mL)
15 (l
g/mL)
20 (lg/mL)
E. coli (25922b)
0.25
0.12
0.12
>32
>32
32
16
2
1
1
2
1
>16
2
2
1
1
4
1
0.05
1
1
8
8
16
8
8
32
8
4
>128
>128
>128
>128
>128
4
4
0.5
1
64
0.5
16
1
0.5
4
64
64
>128
>128
0.5
32
64
32
64
128
0.25
0.25
0.12
<0.12
32
32
16
64
<0.12
2
1
8
2
2
64
8
2
1
4
1
2
8
2
0.25
64
128
8
1
8
4
E. coli (1269687c)
E. coli (1269640)Vs,
E. coli (1269620)Vr,
E. coli (1269621)Vr,
E. coli (1269652)Vr,
E. coli (1269653)Vr,
S. aureus (292213b)
Cs, Gs
Cr,Gr
Cr,Gr
Cr,Gr
Cr,Gr
4
16
8
>0.12
0.25
0.5
0.25
0.5
2
S. aureus (1269615)Vr,
S. aureus (1269616)Ir,
S. aureus (1269617)Vr,
S. aureus (1269618)Ir,
S. aureus (9269619)Or,
S. aureus (1269669)Os
S. aureus (1269670)Os
S. capitis (1269682)
S. epidermidis (1269663)
S. epidermidis (1269675)Or,
S. epidermidis (1269676)Or,
S. epidermidis (1269677)Or,
S. epidermidis (1269680)Or,
S. warneri (1269686)
16
16
8
16
16
2
Cr,Gr
Cr,Gr
Cr,Gr
32
128
Cr ,Gr
Cr ,Gr,Vs
>128
<0.12
<0.12
<0.12
<0.12
16
<0.12
<0.12
<0.12
<0.12
1
0.25
0.25
<0.12
<0.12
<0.12
<0.12
<0.12
<0.12
<0.12
1
0.5
0.8
8
4
4
Gr, Lr
Gr, Lr
Gr
Gr, Lr
1
0.25
8
<0.25
*
Resistance profile: Vr or Vs—vancomycin resistant (VRSA) or vancomycin sensitive, Gr or Gs—gentamicin resistant or sensitive, Cr or Cs—ciprofloxacin resistant or sensitive,
Ir—vancomycin intermediate (VISA), Or or os-oxymycin resistant or sensitive, Lr or Ls—levofloxacin resistant or sensitive, Er or Es—ceftazidime resistant or sensitive.
a
Study ID Number of Focus TechnologiesÒ, unless otherwise indicated.
ATCC Number.
E. coli 0157:H07.
b
c
d
Ceftazimide in the case of E. coli, and linezolide in the case of Staphylococcus.

S. Hanessian et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7097–7101
7101
gentamicin against some strains. However, the combination of N1-
References and notes
(HABA), and 200-O-(phenethylamino)ethyl groups in 30,40-dideoxy
paromomycin (20), led to a remarkably improved inhibitory activ-
ity across the spectrum of resistant organisms, including VRSA and
VISA strains (Table 2).
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Based on our original results of the first antibacterial amphi-
philic aminoglycosides represented by 7 and related analogs,10,14
there is ample opportunity to further explore the synergistic effect
of other 200-O-ethers in combinations with N1-HABA derivatives of
paromomycin and its chemically modified variants. In conclusion,
the knowledge gained from our X-ray studies showing a new mode
of binding of ring III and IV in paromomycin to rRNA fragments, has
allowed us to further explore the potential of amphiphilic amino-
glycosides such as 20 with much improved profiles especially
against resistant bacteria. Studies involving newer modifications
toward more effective and clinically tolerated aminoglycosides will
be reported in due course.17
Acknowledgments
We thank NSERC, FQRNT, and Achaogen Inc. for financial
assistance.
15. See Supplementary data.
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88, 1027.
17. For recent examples of amphiphilic aminoglycoside analogs, see: (a) Bera, S.;
Zhanel, G. G.; Schweizer, F. J. Med. Chem. 2008, 51, 6160; (b) Baussanne, I.;
Bussire, A.; Halder, S.; Ganem-Elbaz, C.; Ouberai, M.; Riou, M.; Paris, J. M.;
Ennifar, E.; Mingeot-Leclercq, M. P.; Découp, J. L. J. Med. Chem. 2010, 53, 119; (c)
Bera, S.; Zhanel, G. G.; Schweizer, F. J. Med. Chem. 2010, 53, 3626.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.09.084.