Syntheses of siderophore-drug conjugates using a convergent thiol-maleimide system

Article abstract of DOI:10.1021/ml300150y

Three siderophore-drug conjugates (sideromycins) were synthesized by preparation of a maleimide linked derivative of the siderophore desferrioxamine B and reacting the corresponding Ga³⁺-complex with freshly prepared thiol-containing antibiotics: loracarbef, ciprofloxacin, and nadifloxacin. The conjugates and their synthetic precursors were tested against a broad panel of bacteria and were found to display Gram-positive selective, growth inhibitory activity (μM), indicating that this approach is suitable for the convergent syntheses and screening of novel sideromycins.

Full text of DOI:10.1021/ml300150y

Letter
pubs.acs.org/acsmedchemlett
Syntheses of Siderophore−Drug Conjugates Using a Convergent
Thiol−Maleimide System
Raul E. Juarez-Hernandez, Patricia A. Miller, and Marvin J. Miller*
́
́
́
Department of Chemistry and Biochemistry, 251 Nieuwland Science Hall, University of Notre Dame, Notre Dame, Indiana 46556,
United States
S
* Supporting Information
ABSTRACT: Three siderophore−drug conjugates (sideromycins) were
synthesized by preparation of a maleimide linked derivative of the
siderophore desferrioxamine B and reacting the corresponding Ga3+-
complex with freshly prepared thiol-containing antibiotics: loracarbef,
ciprofloxacin, and nadifloxacin. The conjugates and their synthetic
precursors were tested against a broad panel of bacteria and were found
to display Gram-positive selective, growth inhibitory activity (μM),
indicating that this approach is suitable for the convergent syntheses and
screening of novel sideromycins.
KEYWORDS: Antibiotic, drug-conjugate, siderophore
iderophores are high affinity, Fe3+-selective chelators
Sproduced by bacteria and fungi. Under iron deficient
conditions, these molecules are secreted into the environment
where they gather essential iron from diverse sources and
deliver it to the producing organism.1−6 The biological
importance of iron has prompted bacteria to develop means
for the recognition of exogenous siderophores in order to gain a
competitive advantage, which in turn has led to the
biosyntheses of naturally occurring siderophore-drug con-
jugates (sideromycins) such as the albomycins,7,8 salmycins,9
and microcins.10,11 These conjugates are modified siderophores
containing an antibiotic portion that is delivered into a
microorganism upon acquisition of the siderophore−Fe3+
complex.17−19 The inability to handle the actively transported
drug might lead to cell death, thus combating siderophore
thievery.
rophore functionalization was the report by Koizumi and
collaborators on the conjugation of desferrioxamine B (DfoB)
with monoclonal antibody OST7 (IgG1) to deliver radio-
gallium 67Ga into tumors of mice,20 for scintigraphic imaging,
by employing three different strategies: (1) using glutaralde-
hyde as a linker, (2) acylation of both building blocks with 2-
pyridyl disulfide and subsequent condensation via a disulfide
bond, and (3) linking a maleimide to DfoB and conjugation
with the thiol-containing antibody (1, Figure 1). In order to
optimize the properties of the conjugates and reduce
radionuclide localization within nontargeted organs, a metab-
Exploiting iron uptake as a biological target has been an
exciting field for the study and development of new methods
that allow the transport of antibacterial agents into pathogenic
cells, and a variety of synthetic sideromycins have been
reported in the literature.12−19 One of the advantages of using
these chelators as carriers is the often selective recognition of
ferri-siderophores by microorganisms. Drug-conjugates of these
molecules have been demonstrated to be highly potent
antibiotic agents, stressing the value of their syntheses and
study.
The assembly of these molecules, however, is a chemically
challenging effort that typically requires manipulation of
protecting groups and tailoring of conditions suitable to the
drug or compound of interest. With the limited availability of
some siderophores, it is highly desirable to minimize the
number of steps needed to accomplish the conjugation, and
thus, a convergent approach would provide a new tool toward
these fascinating molecules. An example of versatile side-
Figure 1. Use of maleimide linkers for the functionalization of
DfoB.20−22
.
Received: June 13, 2012
Accepted: September 4, 2012
Published: September 4, 2012
© 2012 American Chemical Society
799
dx.doi.org/10.1021/ml300150y | ACS Med. Chem. Lett. 2012, 3, 799−803

ACS Medicinal Chemistry Letters
Letter
olizable maleimide linker (2) was later reported,21 indicating
that specific characteristics of the conjugates could be modified
by the linker of choice. Tinianow also reported the use of a
maleimide-containing DfoB (3) to deliver 89Zr using the
monoclonal antibody thiotrastuzumab, for positron emission
tomography (PET) imaging.22
We are interested in the assembly of novel sideromycins
through the previously described thiol-maleimide strategy,
utilizing different siderophores. In this work, we explore the
scope and limitations of this approach by conjugation of
functionalized DfoB 12 (Figure 2) and thiol-containing
antibiotics (e.g., 14) to afford siderophore−drug conjugates
such as Ga-DfoB-ciprofloxacin 17.
further use after aqueous workup. Ampicillin was acylated by
reaction with 5 in THF/H2O/Et3N to give the desired adduct,
6, in 30% yield. Optimized conditions allowed the isolation of
drug-derivatives loracarbef 7 (56% yield), ciprofloxacin 8 (51%
yield), and nadifloxacin 9 (24% yield). The last was obtained
from the EDC·HCl-mediated condensation between nadiflox-
acin and synthetic precursor 4.
The maleimide-functionalized siderophore was obtained by
reacting commercially available DfoB mesylate salt and freshly
prepared NHS ester 10 under buffered conditions to give 11 in
50% yield (Scheme 2). Ga3+-complex 12 was isolated after
refluxing the previous intermediate with Ga(acac)3 in MeOH in
84% yield. We decided to use gallium as a protecting group for
the hydroxamic chelators in DfoB. We were also interested in
the potential role of gallium within our conjugates, since growth
inhibition of Pseudomonas aeruginosa has been reported in the
literature with Ga(NO3)3,25 GaCl3, and Ga-DfoB.26
The removal of the S-trityl protecting group from
intermediates 7−9 was achieved with a mixture of TFA (20%
v/v) and iPr3SiH (2% v/v) in deoxygenated CH2Cl2 (Scheme
2). Sulfur deprotection was monitored by TLC, and the
formation of the corresponding thiol-containing drugs 13−15
was confirmed by LCMS. We were unable to prove the
formation of a thiol-ampicillin derivative from the deprotection
of 6 or to detect any adduct from the conjugation with
maleimide-Ga-DfoB 12. Ga-DfoB-loracarbef sideromycin 16
was obtained in 56% yield from the reaction between freshly
prepared thiol 13, maleimide 12, and DIPEA in deoxygenated
THF. The corresponding Ga-DfoB-ciprofloxacin 17 (24%
yield) and Ga-DfoB-nadifloxacin 18 (21% yield) were prepared
in a similar fashion. The solvent used in the drug conjugation
influenced product formation. When the assembly of 17 was
attempted in CH2Cl2, the desired sideromycin was not detected
even after 70 h.
The novel conjugates and their synthetic precursors were
screened for antibacterial activity against a panel of Gram-
positive and Gram-negative bacteria in an agar diffusion
assay27,28 (Table S1 of the Supporting Information (SI)).
The S-trityl protected antibiotics displayed broad growth
inhibition of bacteria (2 mM), with the exception of
ciprofloxacin derivative 8, where significant levels of precip-
itation were observed in aqueous media due to limited
solubility. In general, Mycobacterium smegmatis and Escherichia
coli were not affected by our compounds. To study the effect of
gallium, we tested Ga(acac)3 and Ga(NO3)3 but no growth
inhibition (at 0.2 mM) was observed under the assay
conditions. Maleimide-functionalized DfoB 11 and the
Figure 2. Use of maleimide−DfoB 12 and thiol−ciprofloxacin 14 in
the synthesis of sideromycin 17.
The attachment of a thiol-containing linker to the drugs of
interest: ampicillin, loracarbef, ciprofloxacin, and nadifloxacin
(representing drugs with different targets) was envisioned by
the use of S-trityl protected acid 423,24 (Scheme 1), which was
obtained from the condensation between 6-bromohexanoic
acid and S-triphenylmethane thiol in the presence of DBU to
afford the desired intermediate in 41% yield. Activated ester 5
was obtained from coupling fragment 4 with NHS using
EDC·HCl. The resulting material could be purified by silica gel
chromatography but was often found to be pure enough for
Scheme 1. Syntheses of Thiol-Containing Antibiotic Precursors
800
dx.doi.org/10.1021/ml300150y | ACS Med. Chem. Lett. 2012, 3, 799−803

ACS Medicinal Chemistry Letters
Letter
Scheme 2. Assembly of Ga-DfoB−Drug Conjugates
corresponding Ga-DfoB complex 12 did not display antibiotic
properties. However, drug-conjugates 16−18 were potent
growth inhibitors, particularly against Gram-positive bacteria
and Mycobacterium vaccae.
After susceptible bacteria were identified, MIC values were
determined in MHII media as well as iron-deficient conditions
(MHII + 2,2′-bipyridine).29 In MHII (Table 1), both S-trityl
(MIC = 3.13 → 25 μM) without enhancing the potency of
Nadi. Consistent with our findings in the agar diffusion assay,
Ga(NO3)3 and Ga-DfoB 12 did not display growth inhibition
(MIC >50 μM). P. aeruginosa (K799/wt) was not inhibited at
the highest concentrations tested, in either MHII or iron-
depleted media (MIC >50 μM, Table S2 of the SI).
Ga-DfoB-loracarbef conjugate 16 retained the antibiotic
activity of the β-lactam drug, while displaying remarkable
inhibition of M. luteus (MIC = 0.001 μM) enhancing the
activity of loracarbef (MIC = 0.39 μM). While this result merits
further study, the finding that M. luteus was strongly inhibited
by 16 is consistent with the fact that it possesses a limited set of
penicillin-binding proteins (PBPs) that render this Gram-
positive bacteria particularly sensitive to β-lactam antibiotics.30
Ga-DfoB-ciprofloxacin 17 displayed reduced inhibition when
compared to 16 (MIC = 31.25 → 50 μM), but enhanced
solubility and therefore improved antibiotic activity over the S-
trityl protected precursor 8. Ga-DfoB-nadifloxacin conjugate 18
(Figure 3) was a strong inhibitor of B. subtilis (MIC = <0.1
μM) and M. vaccae (MIC = 3.13 μM), consistent with the
increased potency of Nadi when compared to Cipro.
Table 1. Minimum Inhibitory Concentration of Compounds
a d
(MIC, μM) Determined in MHII Media −
P.
B. subtilis S. aureus M. luteus
M. vaccae aeruginosa
ATCC
6633
ATCC
10240
IMET
10670
compd
SG511
K799/wt
c
c
c
c
b
b
b
6
7
8
9
2.15
0.39
1.19
1.71
>25
6.25
>25 P
10.4
>25
>50
>50
>50
3.13
>25
0.06
0.24
>25
b
b
b
3.13
2.35
>25
b
b
b
b
>25 P
>25
>25
>25
3.13
>25
25
>25
>25
>25
>25
c
Ga(NO3)3
>25
c
b
b
b
b
12
>50
>50
>50
>50
c
b
b
16
27
9.38
0.001
>50
c
b
b
b
b
17
>50
31.25
>50
>50
c
18
<0.1
0.46
0.008
0.06
12.5
0.78
0.06
0.47
50
>50
>25
>2
c
Lora
0.39
0.20
7.54
c
Nadi
Cipro
0.94
a
MICs were determined by the visual end point broth microdilution
method following CLSI guidelines.29 Reported values are the average
of two sets of duplicates (N = 4). Reported values are the average of
triplicates (N = 3). P, observed precipitation.
b
c
d
protected β-lactams 6 and 7 displayed potent (MIC = 0.39−
3.13 μM) antibiotic activity against Bacillus subtilis, Staph-
ylococcus aureus, and Micrococcus luteus, comparable to that of
loracarbef (MIC = 0.39−0.78 μM). In the case of M. vaccae,
derivative 7 (6.25 μM) was more potent than the parent β-
lactam (>25 μM), possibly due to increased lipophilicity.
The MIC values of ciprofloxacin analog 8 were not
adequately determined because of its limited solubility in
aqueous solution. However, nadifloxacin (Nadi) derivative 9
displayed improved solubility and a range of inhibitory activity
Figure 3. Ga-DfoB-nadifloxacin conjugate 18.
Considering that Ga(NO3)3, Ga(acac)3, and Ga-DfoB 12 did
not display growth inhibition under the different conditions
tested, the observed antibiotic activity of sideromycins 16−18
can be attributed to a functional drug moiety. Our results are
also consistent with bacterial internalization of the conjugates,
as reflected by the growth inhibition of cytoplasmic targets with
fluoroquinolone-based sideromycins (17 and 18). Recently,
801
dx.doi.org/10.1021/ml300150y | ACS Med. Chem. Lett. 2012, 3, 799−803

ACS Medicinal Chemistry Letters
Letter
Rzhepishevska and collaborators reported the antibacterial
properties of gallium citrate (Ga-Cit) and Ga-DfoB against
Gram-positive and Gram-negative bacteria.31 Growth inhibition
by gallium was affected by the metal−ligand and the media
composition. IC90 values for Ga-DfoB against several bacteria
were higher (mM) than the concentrations screened in this
work. To explore the effect of further iron-restricted conditions,
we determined the MIC values in MHII media with the
addition of metal-chelator 2,2′-bipyridine (Table S2 of the SI).
In general, we observed comparable values between both
assays, corroborating the displayed antibiotic activity of our
synthetic compounds. Moderate enhancement (3-fold) was
observed with loracarbef-conjugate 16 against B. subtilis and S.
aureus (MIC = 3.9−7.8 μM). The iron-depleted media was not
conducive for the culturing of M. vaccae, which failed to grow
after two attempts.
In conclusion, we have developed a convergent approach for
the assembly of siderophore−drug conjugates using a thiol−
maleimide strategy. As anticipated, the novel sideromycins
displayed selective antibacterial properties and provided us with
valuable information suitable for the study of these molecules.
Because the siderophore of choice often determines the
spectrum of activity of these conjugates, the described
methodology could be expanded to the design of Gram-
negative antibacterials through the use of an appropriate
chelator.
REFERENCES
■
(1) Miethke, M.; Marahiel, M. A. Siderophore-Based Iron Acquisition
and Pathogen Control. Microbiol. Mol. Biol. Rev. 2007, 71, 413−451.
(2) Boukhalfa, H.; Crumbliss, A. L. Chemical aspects of siderophore
mediated iron transport. Biometals 2002, 15, 325−339.
(3) Andrews, S. C.; Robinson, A. K.; Rodríguez-Quinones, F.
̃
Bacterial iron homeostasis. FEMS Microbiol. Rev. 2003, 27, 215−237.
(4) Sandy, M.; Butler, A. A Microbial Iron Acquisition: Marine and
Terrestrial Siderophores. Chem. Rev. 2009, 109, 4580−4595.
(5) Hider, R. C.; Kong, X. L. Chemistry and biology of siderophores.
Nat. Prod. Rep. 2010, 27, 637−657.
(6) Braun, V.; Hantke, K. Recent insights into iron import by
bacteria. Curr. Opin. Chem. Biol. 2011, 15, 328−334.
(7) Benz, G.; Schroder, T.; Kurz, J.; Wunsche, C.; Karl, W.; Steffen,
̈
̈
G. J.; Pfitzner, J.; Schmidt, D. Konstitution der Deferriform der
Albomycine δ1, δ2 und ε. Angew. Chem., Int. Ed. 1982, 94, 552−553.
(8) Braun, V.; Gunthner, K.; Hantke, K.; Zimmerman, L. Intracellular
̈
Activation of Albomycin in Escherichia coli and Salmonella
typhimurium. J. Bacteriol. 1983, 156, 308−315.
́
(9) Vertesy, L.; Aretz, W.; Fehlhaber, H.-W.; Kogler, H.; Salmycin,
A.-D. Antibiotics from Streptomyces violaceus, DSM 8286, Having a
Siderophore-Aminoglycoside Structure. Helv. Chim. Acta 1995, 78,
46−60.
́
(10) Duquesne, S.; Destoumieux-Garzon, D.; Peduzzi, J.; Rebuffat, S.
Microcins, gene-encoded antibacterial peptides from enterobacteria.
Nat. Prod. Rep. 2007, 24, 708−734.
(11) Nolan, E. M.; Fischbach, M. A.; Koglin, A.; Walsh, C. T.
Biosynthethic Tailoring of Microcin E492m: Post-translational
Modification Affords an Antibacterial Siderophore-Peptide Conjugate.
J. Am. Chem. Soc. 2007, 129, 14336−14347.
ASSOCIATED CONTENT
■
(12) Dong, L.; Roosenberg, J. M., II; Miller, M. J. Total Synthesis of
Desferrisalmycin B. J. Am. Chem. Soc. 2002, 124, 15001−15005.
(13) Bernier, G.; Girijavallabhan, V.; Murray, A.; Niyaz, N.; Ding, P.;
Miller, M. J.; Malouin, F. Desketoneoenactin-Siderophore Conjugates
for Candida: Evidence of Iron Transport-Dependent Species
Selectivity. Antimicrob. Agents Chemother. 2005, 49, 241−248.
(14) Yoganathan, S.; Sit, C. S.; Vederas, J. C. Chemical synthesis and
biological evaluation of gallidermin-siderophore conjugates. Org.
Biomol. Chem. 2011, 9, 2133−2141.
S
* Supporting Information
Experimental procedures of chemistry and microbiology, and
1H and 13C NMR spectra of reported compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mmiler1@nd.edu.
(15) Miller, M. J.; Walz, A. J.; Zhu, H.; Wu, C.; Moraski, G.;
Mollmann, U.; Tristani, E. M.; Crumbliss, A. L.; Ferdig, M. T.;
̈
Checkley, L.; Edwards, R. L.; Boshoff, H. I. Design, Synthesis, and
Study of a Mycobactin-Artemisinin Conjugate That Has Selective and
Potent Activity against Tuberculosis and Malaria. J. Am. Chem. Soc.
2011, 133, 2076−2079.
(16) Roosenberg, J. M., II; Lin, Y. M.; Lu, Y.; Miller, M. J. Studies
and Syntheses of Siderophores, Microbial Iron Chelators, and Analogs
as Potential Drug Delivery Agents. Curr. Med. Chem. 2000, 7, 159−
197.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge the University of Notre Dame and the NIH
(AI 054193) for supporting this work. We appreciate
constructive comments and advice regarding antibacterial
(17) Braun, V.; Pramanik, A.; Gwinner, T.; Koeberle, M.; Bohn, E.
Sideromycins: tools and antibiotics. Biometals 2009, 22, 3−13.
(18) Chu, B. C.; Garcia-Herrero, A.; Johanson, T. H.; Krewulak, K.
D.; Lau, C. K.; Peacock, R. S.; Slavinskaya, Z.; Vogel, H. J. Siderophore
uptake in bacteria and the battle for iron with the host; a bird’s eye
view. Biometals 2010, 23, 601−611.
studies from Dr. Ute Mollman, Jena, Germany. We gratefully
̈
acknowledge the use of the NMR facilities provided by the
Lizzadro Magnetic Resonance Research Center at The
University of Notre Dame (UND) and the mass spectrometry
services provided by The UND Mass Spectrometry &
Proteomics Facility (Mrs. N. Sevova, Dr. W. Boggess, and Dr.
M. V. Joyce; supported by the National Science Foundation
under CHE-0741793).
́ ́
(19) Ji, C.; Juarez-Hernandez, R. E.; Miller, M. J. Exploiting bacterial
iron acquisition: siderophore conjugates. Future Med. Chem. 2012, 4,
297−313.
(20) Koizumi, M.; Endo, K.; Kunimatsu, M.; Sakahara, H.;
Nakashima, T.; Kawamura, Y.; Watanabe, Y.; Saga, T.; Konishi, J.;
Yamamuro, T.; Hosoi, S.; Toyama, S.; Arano, Y.; Yokohama, A. 67Ga-
labeled Antibodies for Immunoscintigraphy and Evaluation of Tumor
Targeting and Drug-Antibody Conjugates in Mice. Cancer Res. 1988,
48, 1189−1194.
(21) Arano, Y.; Matsushima, H.; Tagawa, M.; Koizumi, M.; Endo, K.;
Konishi, J.; Yokoyama, A. A Novel Bifunctional Metabolizable Linker
for the Conjugation of Antibodies with Radionuclides. Bioconjugate
Chem. 1991, 2, 71−76.
ABBREVIATIONS
■
DBU, 1,8-diazabicycloundec-7-ene; DfoB, desferrioxamine B;
Ga-DfoB, Ga3+-complex of DfoB; EDC·HCl, 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide·HCl; LCMS, liquid chro-
matography mass spectrometry; MHII, Mueller−Hinton agar;
MIC, minimum inhibitory concentration; NHS, N-hydrox-
ysuccinimide; THF, tetrahydrofuran; TFA, trifluoroacetic acid;
TLC, thin layer chromatography
802
dx.doi.org/10.1021/ml300150y | ACS Med. Chem. Lett. 2012, 3, 799−803

ACS Medicinal Chemistry Letters
Letter
(22) Tinianow, J. N.; Gill, H. S.; Ogasawara, A.; Flores, J. E.;
Vanderbilt, A. N.; Luis, E.; Vandlen, R.; Darwish, M.; Junutula, J. R.;
Williams, S.-P.; Marik, J. Site-specifically 89Zr-labeled monoclonal
antiodies for ImmunoPET. Nucl. Med. Biol. 2010, 37, 289−297.
(23) Collman, J. P.; Groh, S. E. “Mercaptan-Tail” Porphyrins:
Synthetic Analogues for the Active Site of Cytochrome P-450. J. Am.
Chem. Soc. 1982, 104, 1391−1403.
(24) Moreno, A. Y.; Mayorov, A. V.; Janda, K. D. Impact of Distinct
Chemical Structures for the Development of a Methamphetamine
Vaccine. J. Am. Chem. Soc. 2011, 133, 6587−6595.
(25) Kaneko, Y.; Thoendel, M.; Olakanmi, O.; Britigan, B. E.; Singh,
P. K. The transition metal gallium disrupts Pseudomonas aeruginosa
iron metabolism and has antimicrobial and antibiofilm activity. J. Clin.
Invest. 2007, 117, 877−888.
(26) Banin, E.; Lozinski, A.; Brady, K. M.; Berenshtein, E.;
Butterfield, P. W.; Moshe, M.; Chevion, M.; Greenberg, E. P.;
Banin, E. The potential of desferrioxamine-gallium as an anti-
Pseudomonas therapeutic agent. Proc. Natl. Acad. Sci. U.S.A. 2008,
105, 16761−16766.
(27) General description of the modified Kirby-Bauer agar diffusion
assay used in this work. Afonin, S.; Glaser, R. W.; Berditchevskaia, M.;
Wadhwani, P.; Guhrs, K.-H.; Mollmann, U.; Perner, A.; Ulrich, A. S. 4-
̈
̈
Fluoro-phenylglycine as a Label for 19F-NMR Structure Analysis of
Membrane Associated Peptides. ChemBioChem 2003, 4, 1151−1163.
(28) Murray, P. R.; Baron, E. J.; Pfaller, M. A.; Tenover, F. C.;
Yolken, R. H. Manual of Clinical Microbiology, 7th ed.; American
Society for Microbiology: Washington, DC, 1999.
(29) Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria
that Grow Aerobically, 8th ed.; Clinical and Laboratory Standards
Institute (CLSI): Villanova, PA, 2009; approved standard document
M07-A7.
(30) Young, M.; Artsatbanov, V.; Beller, H. R.; Chandra, G.; Chater,
K. F.; Dover, L. G.; Goh, E.-B.; Kahan, T.; Kaprelyants, A. S.; Kyrpides,
N.; Lapidus, A.; Lowry, S. R.; Lykidis, A.; Mahillon, J.; Markowitz, V.;
Mavromatis, K.; Mukamolova, G. V.; Oren, A.; Rokem, J. S.; Smith, M.
C. M.; Young, D. I.; Greenblatt, C. L. Genome Sequence of the
Fleming Strain of Micrococcus luteus, a Simple Free-Living Actino-
bacterium. J. Bacteriol. 2010, 192, 841−860.
(31) Rzhepishevska, O.; Ekstrand-Hammarstrom, B.; Popp, M.;
̈
Bjorn, E.; Buch, A.; Sjostedt, A.; Antti, H.; Ramstedt, M. The
̈
̈
Antibacterial Activity of Ga3+ Is Influenced by Ligand Complexation as
Well as the Bacterial Carbon Source. Antimicrob. Agents Chemother.
2011, 55, 5568−5580.
803
dx.doi.org/10.1021/ml300150y | ACS Med. Chem. Lett. 2012, 3, 799−803