Antibacterial activity of substituted dibenzo[a,g]quinolizin-7-ium derivatives

Article abstract of DOI:10.1016/j.bmcl.2012.08.123

Berberine is a substituted dibenzo[a,g]quinolizin-7-ium derivative whose modest antibiotic activity is derived from its disruptive impact on the function of the essential bacterial cell division protein FtsZ. The present study reveals that the presence of

Full text of DOI:10.1016/j.bmcl.2012.08.123

Bioorganic & Medicinal Chemistry Letters 22 (2012) 6962–6966
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Antibacterial activity of substituted dibenzo[a,g]quinolizin-7-ium derivatives
Ajit Parhi a, Songfeng Lu a, Cody Kelley b, Malvika Kaul c, Daniel S. Pilch c, Edmond J. LaVoie b,
⇑
a TAXIS Pharmaceuticals Inc., North Brunswick, NJ 08092, USA
b Department of Medicinal Chemistry, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
c Department of Pharmacology, The University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 July 2012
Revised 20 August 2012
Accepted 28 August 2012
Available online 20 September 2012
Berberine is a substituted dibenzo[a,g]quinolizin-7-ium derivative whose modest antibiotic activity is
derived from its disruptive impact on the function of the essential bacterial cell division protein FtsZ.
The present study reveals that the presence of a biphenyl substituent at either the 2- or 12-position of
structurally-related dibenzo[a,g]quinolizin-7-ium derivatives significantly enhances antibacterial
potency versus Staphylococcus aureus and Enterococcus faecalis. Studies with purified S. aureus FtsZ dem-
onstrate that both 2- and 12-biphenyl dibenzo[a,g]quinolizin-7-ium derivatives act as enhancers of FtsZ
self-polymerization.
Keywords:
Antibacterial
Dibenzo[a,g]quinolizinium
FtsZ-targeting
Ó 2012 Elsevier Ltd. All rights reserved.
Staphylococcus aureus
Enterococcus faecalis
Bacterial resistance to current clinical antibacterial drugs has
created a critical need for new therapeutic antibacterial agents
with novel targets and modes of action. Infections associated with
methicillin-resistant Staphylococcus aureus (MRSA) and vancomy-
cin-resistant enterococci (VRE) represent an increasing nosocomial
health concern for both patients and healthcare professionals.1,2
FtsZ is a key protein involved in bacterial cell division (cytokine-
sis).3,4 It is highly conserved among bacterial pathogens and, in
several genetic studies, has been shown to be indispensable.5–8 Cell
division in bacteria occurs at the site of formation of a cytokinetic
Z-ring polymeric structure, which is comprised of FtsZ subunits.9
The essential role that FtsZ plays in bacterial cell division makes
this protein a promising therapeutic target, and recent advances
in the development of small molecules that target FtsZ have been
the subject of several recent reviews.10–13 FtsZ-targeting antibacte-
rial agents can exert their disruptive effects on the Z-ring by either
enhancing or inhibiting FtsZ self-polymerization.14–21
12-position of substituted 5-methylbenzo[c]phenanthridinium
derivatives structurally similar to sanguinarine enhanced relative
antibacterial activity versus both S. aureus and E. faecalis (including
MRSA and VRE strains). In this study, we explore the effect of aryl
substituents at the 2- and the 12-position on the antistaphylo
coccal and antienterococcal activities of a series of dibenzo[a,g]
quinolizin-7-ium
and
8-methyldibenzo[a,g]quinolizin-7-ium
derivatives that are structurally-related to berberine.
Two key intermediates were used for the preparation of the
1-substituted dibenzo[a,g]quinolizin-7-ium salts evaluated for
antibacterial activity in this study, Table 1. Commercially available
4-bromo-3-methoxyphenethylamine was treated with 3,
4-dimethoxybenzoylchloride as outlined in Scheme 1 to form N-
[2-[1-(4-bromo-3-methoxyphenyl)]ethyl]-3,4-dimethoxypheny-
lacetamide derivative, intermediate A. As outlined in Scheme 2,
intermediate A was employed for the synthesis of 1–4 in Table 1.
For the preparation of intermediate B, veratrole was treated with
excess n-butyllithium and then reacted with bromine. The resulting
Berberine (Fig. 1) is a plant alkaloid that exhibits weak antibac-
terial activity, with MIC values typically on the order of 100–
400 lg/mL versus Gram-positive bacteria and >500 lg/mL versus
Gram-negative bacteria.22–24 Recent studies have suggested that
the antibacterial activities of berberine and the structurally-related
benzo[c]phenanthridine alkaloid sanguinarine are derived from
the inhibitory effects of the compounds on FtsZ polymerization
and Z-ring formation.22–24 We have recently demonstrated that
the presence of phenyl or biphenyl substituents at the 1- or
2
12
N
1
4
1
O
O
O
O
11
12
13
8
10
O
11
H3CO
9
N
5
6
O
CH3
6
OCH3
Berberine
Sanguinarine
⇑
Corresponding author.
E-mail address: elavoie@pharmacy.rutgers.edu (E.J. LaVoie).
Figure 1. The structure and numbering of berberine and sanguinarine.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.08.123

A. Parhi et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6962–6966
6963
Table 1
diate B. This intermediate was used as outlined in Scheme 2 for the
preparation of 6–13 in Table 1.
Dibenzo[a,g]quinolizin-7-ium salts synthesized with either
substituent
a 2-aryl or a 12-aryl
Both intermediate A and B were subject to Suzuki coupling con-
ditions using various arylboronates (Scheme 2). In the presence of
POCl3 in acetonitrile, these derivatives provided the requisite pre-
cursors for the formation of various 7-substituted 3,4-dihydro-1-
(3,4-dimethoxybenzyl)isoquinolines. Oxidation in the presence of
palladium on carbon in tetralin provided the aromatized 1-benzyl-
isoquinoline derivatives. Treatment of these derivatives with POCl3
in dimethylformamide yielded the desired 2-substituted 3,4,10,11-
tetramethoxydibenzo[a,g]quinolizin-7-ium chlorides. Alterna-
tively, treatment of these 1-benzylisoquinoline derivatives with
acetic anhydride in the presence of fuming (20%) H2SO4 gave 2-
substituted 8-methyl-3,4,10,11-tetramethoxydibenzo[a,g]quinoli-
zin-7-ium acetylsulfonates.
The synthesis of 12-aryl substituted dibenzo[a,g]quinolizin-7-
ium salts was accomplished as outlined in Scheme 3. Treatment
of either 2,3-dimethoxyphenethylamine or 3,4-dimethoxypheneth-
ylamine with the acid chloride derivative of 2-bromo-3,4-dime-
thoxyphenylacetic acid provide the N-[2-[1-(2,3-dimethoxy-
phenyl)]-ethyl]2-bromo-3,4-dimethoxyphenylacetamide or the
N-[2-[1-(3,4-dimethoxyphenyl)]ethyl]-2-bromo-3,4-dimethoxyphenyl-
acetamide, respectively. These bromo derivatives were reacted under
Suzuki coupling conditions with several arylboronates, cyclized in the
presence of POCl3 in acetonitrile and oxidized to their respective 1-ben-
zylisoquinoline derivatives. Treatment of these derivatives with POCl3 in
dimethylformamide yielded the desired 12-substituted dibenzo
[a,g]quinolizin-7-ium chlorides, 14 and 16. Alternatively, treatment of
these 1-benzylisoquinoline derivatives with acetic anhydride in the
presence of fuming (20%) H2SO4 gave the 12-substituted 8-meth-
yldibenzo[a,g]quinolizin-7-ium acetylsulfonates, 15 and 17.
These dibenzo[a,g]quinolizin-7-ium derivatives were evaluated
for their antibacterial activity against methicillin-sensitive Staphy-
lococcus aureus (MSSA) and methicillin-resistant Staphylococcus
aureus (MRSA) as well as vancomycin-sensitive Enterococcus faecal-
is (VSE) and vancomycin-resistant Enterococcus faecalis (VRE). Their
relative antibacterial activities are listed in Table 2. Berberine did
not exhibit appreciable antibiotic activity when evaluated against
the strains of S. aureus or E. faecalis used in this study. Compounds
1–4 exhibit significant antibacterial activity against MSSA. The 2-
(4-toluyl) derivatives 3 and 4 are more active than the 2-phenyl
derivatives 1 and 2 against both S. aureus strains and VSE. The pres-
ence or absence of an 8-methyl substituent has a modest effect on
antibacterial activity among these trimethoxy derivatives, with
this effect being variable and typically reflected by a two-fold dif-
ference in MIC values.
Antibacterial activities of the 2-aryl 3,4,10,11-tetrame-
thoxydibenzo[a,g]quinolizin-7-ium derivatives 5–13 were also
consistently associated with an increase in antibacterial activity
against both S. aureus strains relative to 1 and 2. The effect of an
8-methyl substituent among these tetramethoxy derivatives on
antibacterial activity is modest and, in general, tends toward only
a slightly greater antibacterial effect. Only in the case of 9 when
evaluated against VRE is a slightly greater antibiotic activity ob-
served relative to its 8-methyl derivative, 10.
X2
OCH3
R4
X12
H3CO
H3CO
N+
R8
X2
R4
R8
X12
H
1
H
H
H
H
2
–CH3
H
H
H
H
H
H
H
H
H
H
H
3
CH3
CH3
4
H
–
–CH3
H
5
OCH3
–
6
–CH3
H
OCH3
–
7
C(CH3)3
C(CH3)3
OCH3
–
8
–CH3
H
OCH3
–
9
OCH3
–
10
11
–CH3
CH(CH3)2
OCH3
–
OCH3
–
12
13
H
H
H
OCH3
–
–CH3
OCH3
–
14
15
H
H
H
OCH3
–
–CH3
H
OCH3
16 –OCH3
17 –OCH3
H
H
–CH3
There was a notable difference between the 3,10,11-trimeth-
oxy- and 3,4,10,11-tetramethoxydibenzo[a,g]quinolizin-7-ium
derivatives with regard to activity against E. faecalis. None of the
1,4-dibromo-2,3-dimethoxy-benzene was then treated with
n-butyllithium and DMF to provide the intermediate 4-bromo-
2,3,-dimethoxybenzaldehyde in Scheme 1. Condensation of this
benzaldehyde with nitromethane provided the 2-nitroethylene
intermediate, which was reduced with NaBH4 and then treated
with Zn powder in acetic acid to yield 2-bromo-2,3-dimethoxy-
phenethylamine. Treatment of this phenethylamine with 3,4-dim-
ethoxyphenylacetylchloride provided the N-[2-[1-(4-bromo-2,
3-dimethoxyphenyl)]ethyl]phenylacetamide derivative as interme-
trimethoxy derivatives has an MIC value less than 64 lg/mL
against the vancomycin-resistant strain. Interestingly, several of
the 2-aryl-3,4,10,11-tetramethoxy derivatives exhibited enhanced
activity toward both strains of E. faecalis. The 8-isopropyl deriva-
tive, 11, was the most potent dibenzo[a,g]quinolizin-7-ium analog
evaluated in both strains of S. aureus and E. faecalis.
Comparison of the antibiotic activities of 9 and 10 with the 1-
naphthyl derivatives (12,13) and the 12-biphenyl derivatives

6964
A. Parhi et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6962–6966
Br
OMe
H2N
MeO
MeO
O
a
HN
MeO
MeO
Cl
OMe
Intermediate A
O
Br
Br
OMe
OMe
H2N
O2N
CHO
Br
MeO
MeO
O
OMe
OMe
OMe
OMe
a
OMe
OMe
c,d
b
HN
MeO
MeO
Cl
Br
O
Br
Intermediate B
Scheme 1. Preparation of intermediate A and intermediate B. Reagents and conditions: (a) 2M Na2CO3, CHCl3, 0 °C; (b) NH4OAc, CH3NO2, glacial acetic acid, 120 °C, 72%; (c)
NaBH4, 1,4-dioxane/EtOH (2:1), 91%; (d) acetic acid/Zn powder, 57%.
R
R
OCH3
Br
OCH3
H3CO
X
OCH3
H3CO
H3CO
O
d
b,c
a
H3CO
H3CO
O
N
X
H3CO
HN
X
HN
X = H or OCH3
Intermediate A; X = H
Intermediate B; X = OCH3
R
e
OCH3
X
f
R
H3CO
OCH3
N
H3CO
H3CO
H3CO
X
N
1, 3 X = H
5, 7, 9, 12 X = OCH3
CH3
OCH3
OCH3
2, 4 X = H
6, 8, 10, 13 X = OCH3
H3CO
H3CO
N
CH
CH3
H3C
11
Scheme 2. Methods used for the preparation of 2-substituted dibenzo[a,g]quinolizin-7-ium salts. Reagents and conditions: (a) R-B(OH)2, K2CO3, Pd (PPh3)4, dioxane:H2O
(3:1), 100 °C; (b) POCl3, ACN, reflux, 1–2 h; (c) Pd/C, tetralin, 210–220 °C; (d) POCl3, DMF, HCl; (e) acetic anhydride, fuming H2SO4; (f) isobutyric anhydride, fuming H2SO4.
(14,15) reveals that these compounds exhibit similar activity. The
relative antibiotic activities of 14 and 15 tend to be somewhat less
than 9 and 10 against the resistant S. aureus and E. faecalis strains.
A similar trend is observed in comparing the antibacterial activities
of 12-biphenyl-2,3,10,11-trimethoxydibenzo[a,g]quinolizin-7-ium
derivatives 16 and 17 with the 2-biphenyl-3,4,10,11-tetrame-
thoxydibenzo[a,g]quinolizin-7-ium derivatives 9 and 10.
20 lg/mL. The time-dependent increase in light scattering
observed in the presence of vehicle only is reflective of FtsZ self-
polymerization in the absence of test compound. Significantly,
the increase in light scattering observed in the presence of 11 is
greater than that in the absence of compound, with the extent of
this light scattering enhancement being dependent on compound
concentration. The lack of light scattering change associated with
A 90°-angle light scattering assay was used to monitor the im-
pact, if any, of select dibenzo[a,g]quinolizin-7-ium compounds on
the dynamics of self-polymerization by purified S. aureus FtsZ (SaF-
tsZ). In this assay, FtsZ polymerization is detected in solution by a
time-dependent increase in light scattering. As an illustrative
example for a dibenzo[a,g]quinolizin-7-ium compound with an
aryl (biphenyl) substitution at the 2-position, Figure 2A shows
the time-dependent light scattering profiles of SaFtsZ in the
20 lg/mL 11 in the absence of FtsZ (Fig. 2A) confirms that the
enhanced light scattering induced by 11 in the presence of FtsZ re-
flects a corresponding stimulation of FtsZ self-polymerization and
not simply compound aggregation or precipitation.
As an illustrative example for the impact on SaFtsZ polymeriza-
tion of a dibenzo[a,g]quinolizin-7-ium compound with an aryl
(biphenyl) substitution at the 12-position, Figure 2B shows the
time-dependent light scattering profiles of SaFtsZ in the absence
absence and presence of 11 at concentrations of 10
l
g/mL and
and presence of 17 at a concentration of 20 lg/mL. Oxacillin is also

A. Parhi et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6962–6966
6965
Br
Br
Br
H3CO
H3CO
H3CO
H3CO
COCl
H3CO
H3CO
a
Cl
b,c,d
e
OH
Y
Y
OCH3
Br
R
OCH3
H3CO
O
H3CO
f,g,h
i
X
X
HN
N
H3CO
H3CO
Y
j
Y
OCH3
X
OCH3
X
R
R
H3CO
H3CO
H3CO
H3CO
N
N
Cl
O
CH3COSO2O
Me
14 X = OCH3; Y = H
16 X = H; Y = OCH3
15 X = OCH3; Y = H
17 X = H; Y = OCH3
Scheme 3. Methods used for the preparation of 12-substituted dibenzo[a,g]quinolizin-7-ium salts. Reagents and conditions: (a) 12N HCl, toluene, 88%; (b) KCN, Me2SO, 90%;
(c) HOAC, H2O, conc. H2SO4, quant.; (d) (COCl)2, DCM, 2 h; (e) 2M Na2CO3, CHCl3, 0 °C; (f) R-B(OH)2, K2CO3, Pd (PPh3)4, dioxane:H2O (3:1), 100 °C; (g) POCl3, ACN, reflux, 1-2 h;
(h) Pd/C, tetralin, 210–220 °C; (i) POCl3, DMF, HCl; (j) acetic anhydride, fuming H2SO4
included (at 20
l
g/mL) as a control non-FtsZ-targeting antibiotic.
zation, an expected result given that the antibacterial target of
oxacillin is the bacterial cell wall rather than FtsZ. A comparison
Note that oxacillin exerts a negligible impact on SaFtsZ polymeri-
of the light scattering profiles of 11 and 17 at 20 lg/mL (the green
profiles in Fig. 2A and B) reveals the following two differential fea-
tures: (i) 17 stimulates FtsZ polymerization more rapidly than 11,
as reflected by the light scattering profile of 17 reaching a plateau
earlier than that of 11. (ii) After reaching a plateau, the light scat-
tering profile of 17 also undergoes a time-dependent decrease, sug-
gestive of a corresponding time-dependent dissociation from
larger to smaller FtsZ polymers or polymeric bundles. These two
differential features may contribute, at least in part, to the reduced
activities of 17 relative to 11 against both the MSSA and MRSA
strains tested.
Stimulation of FtsZ polymerization has been shown to be the
antibacterial mechanism of action for agents such as the substi-
tuted benzamides (e.g., PC190723).14,17,18 In addition, FtsZ has been
implicated as the antibacterial target of the naturally occurring
dibenzoquinolizinium berberine, although the antibacterial po-
tency of berberine is substantively weaker than that of our substi-
tuted dibenzoquinolizinium compounds.23 Viewed as a whole, the
light scattering results point to the stimulation of FtsZ polymeriza-
tion dynamics as underlying the antibacterial activity of the 2- and
12-substituted dibenzo[a,g]quinolizin-7-ium compounds.
In summary, the presence of an aryl substituent at either the
2- or 12-position of tetramethoxy dibenzoquinolizinium signifi-
cantly increases FtsZ-targeted antistaphylococcal and antientero-
coccal activity relative to berberine, with the compounds having
notable antibacterial activity against multidrug-resistant strains
of both MRSA and VRE. Against VRE, all of the biphenyl-substi-
tuted derivatives have MIC values lower than those of the clinical
antibiotics used as controls in this study. Studies are in progress
to develop suitable formulations for assessment of their relative
antibacterial activity in vivo using appropriate animal models of
infection.
Table 2
Antistaphylococcal and antienterococcal activities of dibenzo[a,g]quinolizin-7-ium
salts with either 2- or 12-aryl substituents
MICa
(l
g/mL)
S. aureus
8325-4
(MSSA)
S. aureus
E. faecalis
ATCC 19433
(VSE)
E. faecalis
ATCC 51575
(VRE)
ATCC 33591
(MRSA)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
8
8
2
4
4
2
4
1
2
1
0.5
4
1
2
1
2
1
32
>64
8
8
8
8
4
2
2
2
0.5
2
2
8
4
4
4
32
>64
16
8
16
8
4
4
8
4
2
8
4
8
16
8
4
>64
8
1
64
>64
>64
>64
32
16
8
4
4
8
2
8
8
16
16
32
32
>64
>64
>64
>64
>64
>64
17
Berberine
Oxacillin
Vancomycin
Erythromycin 0.13
Tetracycline
Clindamycin
>64
0.06
1
>64
>64
2
>64
64
>64
1
0.5
2
0.06
0.03
a
Minimum inhibitory concentration (MIC) assays were conducted in accordance
with Clinical Laboratory Standards Institute (CLSI) guidelines for broth microdilu-
tion.25 MIC is defined as the lowest compound concentration at which bacterial
growth is P90% inhibited.

6966
A. Parhi et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6962–6966
1.2
1
1.2
Vehicle
17
Oxacillin
Vehicle + SaFtsZ
A
B
10 µg/mL 11 + SaFtsZ
20 µg/mL 11 + SaFtsZ
20 µg/mL 11 Alone
1
0.8
0.6
0.4
0.2
0
0.8
0.6
0.4
0.2
0
0
10
20
30
40
50
60
0
10
20
30
Time (min)
40
50
60
Time (min)
Figure 2. Impact of select dibenzo[a,g]quinolizin-7-ium compounds on the self-polymerization of purified S. aureus FtsZ (SaFtsZ), as determined by monitoring time-
dependent changes in 90°-angle light scattering. (A) Light scattering profiles of SaFtsZ (8.3 M) in the presence of DMSO vehicle (black) or 11 at a concentration of either 10
(red) or 20 (green) g/mL. For comparative purposes, the corresponding light scattering profile of 20 g/mL 11 alone (violet) is also included as a no-protein control. (B) Light
scattering profiles of SaFtsZ (8.3 M) in the presence of DMSO vehicle (black) or 20 g/mL of either 17 (green) or the comparator antibiotic oxacillin (red). Experiments were
conducted at 25 °C in solution containing 50 mM TrisꢀHCl (pH 7.4), 50 mM KCl, 2 mM magnesium acetate, 1 mM CaCl2, and 1 mM GTP. GTP was combined with vehicle, test
compound, or control drug, and the reactions were initiated by addition of the protein. The reactions (150 L total volume) were continuously monitored in quartz ultra-
l
l
l
l
l
l
micro cells (pathlength of 10 mm in the excitation direction and 2 mm in the emission direction) using an AVIV ATF 105 spectrofluorimeter, with the excitation and emission
wavelengths set at 470 nm (at which the dibenzo[a,g]quinolizin-7-ium compounds absorb little or no light) and the corresponding excitation and emission bandwidths set at
2 nm. Readings were acquired in 5-second intervals with a corresponding time constant of 1 second.
5. Addinall, S. G.; Bi, E.; Lutkenhaus, J. J. Bacteriol. 1996, 178, 3877.
6. Pinho, M. G.; Errington, J. Mol. Microbiol. 2003, 50, 871.
Acknowledgments
7. Lutkenhaus, J.; Addinall, S. G. Annu. Rev. Biochem. 1997, 66, 93.
8. Lowe, J.; van den Entm, F.; Amos, L. A. Annu. Rev. Biophys. Biomol. Struct. 2004,
33, 177.
This study was supported by research agreements between
TAXIS Pharmaceuticals, Inc. and both Rutgers, The State University
of New Jersey (E.J.L.) and the University of Medicine and Dentistry
of New Jersey (D.S.P). We would like to thank Drs. Steve Tuske and
Eddy Arnold (Center for Advanced Biotechnology and Medicine,
Rutgers University) for their assistance with the expression and
purification of the S. aureus FtsZ protein. S. aureus 8325-4 was
the generous gift of Dr. Glenn W. Kaatz (John D. Dingell VA Medical
Center, Detroit, MI). The Brucker Avance III 400 MHz NMR spec-
trometer used in this study was purchased with funds from NCRR
Grant No. 1S10RR23698-1A1. Mass spectrometry was provided by
the Washington University Mass Spectrometry Resource with sup-
port from the NIH National Center for Research Resources Grant
No. P41RR0954.
9. Lock, R. L.; Harry, E. J. Nat. Rev. 2008, 7, 324.
10. Kapoor, S.; Panda, D. Expert Opin. Ther. Targets 2009, 13, 1037.
11. Foss, M. H.; Eun, Y.-J.; Weibel, D. B. Biochemistry 2011, 50, 7719.
12. Schaffner-Barbero, C.; Martin-Fontecha, M.; Chacon, P.; Andreu, J. M. ACS Chem.
Biol. 2012, 7, 269.
13. Margalit, D. N.; Romberg, L.; Mets, R. B.; Hebert, A. M.; Mitchision, T. J.;
Kirschner, M. W.; RayChaudhuri, D. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
11821.
14. Andreu, J. M.; Schaffner-Barbero, C.; Huecas, S.; Alonso, D.; Lopez-Rodriguez,
M. L.; Ruiz-Avila, L. B.; Núñez-Ramírez, R.; Llorca, O.; Martín-Galiano, A. J. J.
Biol. Chem. 2010, 285, 14239.
15. Beuria, T. K.; Santra, M. K.; Panda, D. Biochemistry 2005, 44, 16584.
16. Domadia, P. N.; Bhunia, A.; Sivaraman, J.; Swarup, S.; Dasgupta, D. Biochemistry
2008, 47, 3225.
17. Haydon, D. J.; Bennett, J. M.; Brown, D.; Collins, I.; Galbraith, G.; Lancett, P.;
Macdonald, R.; Stokes, N. R.; Chauhan, P. K.; Sutariya, J. K.; Nayal, N.; Srivastava,
A.; Beanland, J.; Hall, R.; Henstock, V.; Noula, C.; Rockley, C.; Czaplewski, L. J.
Med. Chem. 2010, 53, 3927.
18. Haydon, D. J.; Stokes, N. R.; Ure, R.; Galbraith, G.; Bennett, J. M.; Brown, D. R.;
Baker, P. J.; Barynin, V. V.; Rice, D. W.; Sedelnikova, S. E.; Heal, J. R.; Sheridan, J.
M.; Aiwale, S. T.; Chauhan, P. K.; Srivastava, A.; Taneja, A.; Collins, I.; Errington,
J.; Czaplewski, L. G. Science 2008, 321, 1673.
19. Kumar, K.; Awasthi, D.; Lee, S. Y.; Zanardi, I.; Ruzsicska, B.; Knudson, S.; Tonge,
P. J.; Slayden, R. A.; Ojima, I. J. Med. Chem. 2011, 54, 374.
20. Läppchen, T.; Hartog, A. F.; Pinas, V. A.; Koomen, G. J.; den Blaauwen, T.
Biochemistry 2005, 44, 7879.
21. Urgaonkar, S.; La Pierre, H. S.; Meir, I.; Lund, H.; RayChaudhuri, D.; Shaw, J. T.
Org. Lett. 2005, 7, 5609.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.
08.123.
References and notes
1. Leavis, H. L.; Willems, R. J. L.; Top, J.; Spalburg, E.; Mascini, E. M.; Fluit, A. C.;
Hoepelman, A.; de Neeling, A. J.; Bonten, M. J. M. Emerg. Infect. Dis. 2003, 9,
1108.
2. Klevens, R. M.; Morrison, M. A.; Nadle, J.; Petit, S.; Gershman, K.; Ray, S.;
Harrison, L. H.; Lynfield, R.; Dumyati, G.; Townes, J. M.; Craig, A. S.; Zell, E. R.;
Fosheim, G. E.; McDougal, L. K.; Carey, R. B.; Fridkin, S. K. J. Am. Med. Assoc.
2007, 298, 1763.
22. Ball, A. R.; Casadei, G.; Samosorn, S.; Bremner, J. B.; Ausubel, F. M.; Moy, T. I.;
Lewis, K. ACS Chem. Biol. 2006, 1, 594.
23. Boberek, J. M.; Stach, J.; Good, L. PLoS One 2010, 5, e13745.
24. Iwasa, K.; Kamigauchi, M.; Ueki, M.; Taniguchi, M. Eur. J. Med. Chem. 1996, 31,
469.
25. CLSI Methods for dilution antimicrobial sucseptibility tests for bacteria that
grow aerobically; approved standard-eighth edition; Clinical and Laboratory
Standards Institute: Wayne, PA, 2009.
3. Addinall, S. G.; Holland, B. J. Mol. Biol. 2002, 318, 219.
4. Margolin, W. Nat. Rev. Mol. Cell Biol. 2005, 6, 862.