Function of Fimsbactin B as an Acinetobacter-Selective Antibiotic Delivery Vehicle

Article abstract of DOI:10.1021/acs.orglett.1c01786

The ability of fimsbactin B, a natural siderophore of Acinetobacter baumannii, to function as an antibiotic delivery vehicle was investigated by synthesizing three structurally diversified fimsbactin B-cefaclor conjugates. Their antimicrobial activities w

Full text of DOI:10.1021/acs.orglett.1c01786

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Letter
Function of Fimsbactin B as an Acinetobacter-Selective Antibiotic
Delivery Vehicle
Do Young Kim and Hak Joong Kim*
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ABSTRACT: The ability of fimsbactin B, a natural siderophore of
Acinetobacter baumannii, to function as an antibiotic delivery
vehicle was investigated by synthesizing three structurally
diversified fimsbactin B−cefaclor conjugates. Their antimicrobial
activities were Acinetobacter-selective and up to 128-fold more
potent than that of cefaclor alone. This activity enhancement
originated from the fimsbactin-B-dependent active uptake of
cefaclor. Thus, fimsbactin-B-based antibiotic delivery can be an
effective approach in combating antibiotic-resistant Acinetobacter
infections.
he siderophore−antibiotic conjugate, typically called
Tsideromycin, has garnered significant attention as an
effective therapeutic modality for overcoming the antibiotic
resistance of pathogenic bacteria.1−3 Siderophores are metal-
chelating natural products, and most bacteria use them for
active iron assimilation in iron-depleted environments, such as
infection sites.4,5 The uptake of an iron−siderophore complex
mediates its specific interaction with the cognate receptor.
Sideromycins use such specific iron entry pathways by
disguising themselves as benign iron carriers, of which the
mechanism is reminiscent of the Trojan horse. This strategy
would be particularly effective when antibiotic resistance is
associated with reduced outer membrane permeability,6−8
which is typically observed in Gram-negative pathogens, such
as Pseudomonas aeruginosa and Acinetobacter baumannii. The
recent U.S. Food and Drug Administration (FDA) approval of
cefiderocol, which is a sideromycin developed by Shionogi, for
treating patients with complicated urinary tract infections
caused by Gram-negative pathogens, supports the efficiency of
siderophore-mediated intracellular antibiotic delivery.9
A. baumannii has recently caused great concerns, particularly
in nosocomial settings, owing to its rapid antibiotic resistance
development.10,11 Because reduced membrane permeability is
one of the key resistance mechanisms of A. baumannii,12 the
siderophore−antibiotic conjugate may be a promising strategy
for combating this pathogen. While none of the natural
siderophores of A. baumannii (Figure 1)13−16 has yet to be
exploited as an antibiotic delivery vehicle, the principle has
been demonstrated using synthetic analogues of fimsbactin
developed by Miller and co-workers (vide infra).31 Herein, we
investigated the ability of fimsbactin B (FimB) to enhance the
activity of the conjugated antibiotic by facilitating its active
uptake over the membrane barrier of A. baumannii.
Figure 1. Structures of natural siderophores of A. baumannii.
Received: May 28, 2021
Published: June 16, 2021
https://doi.org/10.1021/acs.orglett.1c01786
© 2021 American Chemical Society
Org. Lett. 2021, 23, 5256−5260
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Owing to the structural complexity of natural siderophores,
simple bidentate ligands, such as catechol or ortho-pyridone,
are often employed as antibiotic carriers. However, natural
siderophores have unique advantages, such as an effective
cellular entry as a result of an optimized siderophore−receptor
interaction, a possibility for cytoplasmic delivery of a warhead,
and/or species-selective characteristics that minimize collateral
damage to beneficial microbiota. In using a natural siderophore
as an antibiotic delivery vehicle, one of the key considerations
is the selection of an appropriate conjugation site that does not
disturb the siderophore−receptor interactions, which is
essential for maximizing the uptake efficiency. In that respect,
the structural features of natural sideromycins often serve as
the basis for designing novel antibiotic conjugates (Figures S1
and S2 of the Supporting Information).17−19 When a natural
model is not available, information regarding the siderophore−
receptor complex structures,20 established structure−function
relationships,21,22 or synthetic accessibility23−25 can be
considered for the rational design of siderophore−antibiotic
conjugates (Figure S2 of the Supporting Information).
Our previous study on the structure−function relationship
of FimB revealed the stereoselective nature of the cognate
transporter system.26 However, constructive information for
selecting a suitable antibiotic conjugation site on FimB was
practically unavailable. Therefore, we undertook a semi-
shotgun approach through which multiple positions were
picked without considerable preconception. Specifically, three
positions, C-4, C-22, and C-32 (Figure 1), were selected for
manipulation because these sites were moderately spread apart
allowing for sufficient structural variation and were less likely
to disturb iron−FimB complexation. In addition, cefaclor (Cec,
17), a second-generation cephalosporin inhibiting the biosyn-
thesis of the periplasmic peptidoglycan layer, was chosen as the
model antibiotic, considering the proposed iron delivery by
FimB up to the periplasm.15,26
Although the construction of the fimsbactin skeleton largely
depended upon our previously established synthetic proto-
col,26,27 several key alterations were implemented to
successfully generate the corresponding antibiotic conjugates.
First, for the functionalization at C-4 and C-22, a reactive
handle must be introduced on the catechol moiety. Nolan and
co-workers prepared enterobactin-based conjugates through
the derivatization of the cognate site as a carboxylic acid,
although it required a slightly prolonged synthetic sequence.18
For simpler precursor preparation as well as facile late-stage
functionalization, we introduced an iodide because of its
resistance to the reaction conditions employed for the
fimsbactin skeleton construction as well as its high reactivity
for various transition-metal-catalyzed cross-coupling reactions.
The required iodide could be easily incorporated through
regioselective iodination of o-vanillin (Scheme 1A).28 After the
cleavage of the methyl ether releasing catechol 6, subsequent
synthetic elaboration was performed as previously de-
scribed.26,27 Briefly, the vicinal diol was protected with o-
xylene, and subsequent Pinnick oxidation provided acid 7a.
This intermediate was then coupled with L-threonine methyl
ester, and subsequent dehydrative cyclization catalyzed by
molybdenum oxide formed an oxazoline ring. Lastly, treatment
with potassium trimethylsilanolate provided excellent yields of
corresponding potassium carboxylate salt 8a.
Scheme 1. Preparation of Building Blocks 8a and 10a
prepared from a known putrescine derivative (9)29 via amide
coupling with N-Fmoc- and O-TBDMS-protected L-serine,
followed by the removal of the Fmoc moiety (Scheme 1B).
The synthesis of FimB−Cec conjugates was continued
through combinatorial coupling between oxazoline carboxylate
(8a/8b) and putrescine derivative (10a/10b) building blocks,
as depicted in Scheme 2. Following desilylation, the resulting
intermediates (11a/11b/11c) were treated with catecholic
acid chlorides (12a/12b) to complete the construction of
corresponding FimB skeletons (13a/13b/13c).
At this stage, two different synthetic routes were formulated
to attach the linkers. We designed two separate linkers (14 and
15), whose termini were equipped with benzyl esters suitable
for conjugation with cefaclor. Alkyne linker 14 was easily
attached to iodine-containing intermediates, 13a and 13b,
through the Pd(0)/Cu(I)-catalyzed Sonogashira reaction,
yielding compounds 16a and 16b, respectively. For introduc-
tion of the linker for C-32 derivatization, the Boc protective
group of compound 13c was removed under acidic conditions,
and the subsequent amide bond formation with linker 15
produced compound 16c.
For conjugation with cefaclor (17), all precursors (16a/
16b/16c) were subjected to global deprotection under Pd(0)-
catalyzed hydrogenolysis conditions, during which complete
reduction of the alkynes in compounds 16a and 16b was
accompanied. The resulting terminal acids were then
condensed with N-hydroxysuccinimide (NHS) to produce
corresponding NHS esters. Each of these activated esters was
treated with cefaclor (17), and chemoselective amide linkage
formation among them was observed on the basis of high-
performance liquid chromatography (HPLC) analysis (Figure
S3 of the Supporting Information). After purification through
semi-preparative HPLC, all desired FimB−Cec conjugates
(18a/18b/18c) could be successfully secured. Notably,
significant decomposition of the FimB−Cec conjugates
involving hydrolytic oxazoline ring opening was observed
when common ion-pairing agents, such as trifluoroacetic and
formic acids, were included in the eluent solvents used in
HPLC purification. However, this problem could be resolved
using volatile ammonium bicarbonate as the ion-pairing agent
(pH 7.2, 10 mM aqueous solution).
Precursor 10a was designed for late-stage functionalization
at C-32, which would involve a linker attachment via amide
bond formation, following Boc deprotection. It could be
The antimicrobial activities of all three FimB−Cec
conjugates against A. baumannii ATCC 17978 possessing the
fimsbactin gene cluster were evaluated on the basis of the
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Scheme 2. Synthesis of Three FimB−Cec Conjugates 18a, 18b, and 18c
minimal inhibitory concentration (MIC) determination.
Assessing the level of impact of FimB attachment as well as
the selected conjugation site on the activity was of particular
interest. First, an assay was conducted under iron-deficient
conditions created by adding 300 μM 2,2′-bipyridyl (DP), an
iron sequester, to cation-adjusted Mueller−Hinton broth II
(CAMHB) media. As shown in entry 1 of Table 1, the MICs of
compounds 18a, 18b, and 18c were determined to be 0.5, 1.0,
and 2.0 μg/mL, respectively, indicating that the C-4 position
may be the best antibiotic conjugation site among those tested,
albeit marginally. Importantly, the MIC of compound 18a was
128-fold smaller than that of cefaclor alone (64 μg/mL),
demonstrating the ability of FimB to function as an effective
antibiotic delivery vehicle in targeting A. baumannii ATCC
17978. To investigate whether this enhanced activity of
compounds18a−18c over cefaclor is based on the FimB-
dependent cellular delivery, an analogous assay was conducted
under iron-replete conditions, where expression of the genes
for fimsbactin utilization would be suppressed. As predicted, a
significant increase was observed in the MIC values for all
conjugates (18a, 16 μg/mL; 18b, 16 μg/mL; and 18c, 64 μg/
mL) (entry 2 of Table 1). In addition, treatment with a 1:1
combination of FimB and cefaclor did not exhibit any notable
activity (MIC > 64 μg/mL), confirming the active uptake of
cefaclor by fimsbactin conjugation. Furthermore, a time-kill
experiment was conducted to demonstrate that the action of
compound 18a was bactericidal, typical of cephalosporin
antibiotics, such as cefaclor (Figure S4 of the Supporting
Information). This result evidently confirms that the cefaclor
segment is responsible for the antimicrobial activity of
compound 18a.
The species selectivity of compounds 18a−18c was then
investigated using a number of Gram-negative bacteria. First,
when two different Acinetobacter species, A. baumannii ATCC
19606 and A. nosocomialis, lacking the fimsbactin gene cluster,
were tested under iron-deficient conditions, a conspicuous
increase in MIC was observed (entries 3 and 5 of Table 1)
compared to those for A. baumannii ATCC 17978. However,
the activities of all conjugates were higher than those of
cefaclor alone and were dependent upon iron availability
(entry 3 versus entry 4 and entry 5 versus entry 6 of Table 1).
This result reveals that the alternative outer membrane
a
Table 1. Antimicrobial Activity Assay Results
DP
concentration
b
entry
strain
(μM)
18a
0.5
16
18b
18c
Cec
1
2
A. baumannii
ATCC
17978
300
0
1
16
2
64
64
>64
3
4
A. baumannii
ATCC
19606
300
0
16
>64
16
>64
16
>64
>64
>64
5
6
A. nosocomialis
ATCC
17903
150
0
16−32
>64
16
>64
16
>64
>64
>64
7
8
9
10
E. coli K12
300
0
300
0
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
64
64
>64
>64
P. putida
ATCC
c
12633
a
MIC values (μg/mL) were determined after a 48 h culture at 37 °C
using the CAMHB medium containing the indicated concentration of
DP. Although the growth of A. baumannii ATCC 17978 was not
b
completely inhibited at 300 μM DP, it was still capable of expressing
the fimsbactin uptake genes. The DP concentrations of the other
strains were adjusted to roughly match their growth rates to that of A.
c
baumannii ATCC 17978. P. putida was cultured at 30 °C.
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siderophore receptor with relaxed substrate specificity present
in these two bacteria might be capable of recognizing FimB,
leading to the intracellular uptake of compounds 18a−18c. In
the case of A. baumannii ATCC 19606, either PiuA or PirA,
known to be responsible for uptake of monocatechol
sideromycins, such as cefiderocol,34 seems likely to be a
candidate. Interestingly, two other bacteria, Escherichia coli and
Pseudomonas putida, were found to be resistant to compounds
18a−18c and cefaclor alone, irrespective of iron availability
(entries 7−10 of Table 1). This result strongly suggests that
FimB is an Acinetobacter-selective antibiotic carrier.
Moreover, we anticipate the approaches described herein to be
readily adopted by other researchers attempting to identify
potent sideromycins with maximized intracellular delivery,
thereby contributing to the resolution of antibiotic resistance
problems.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01786.
In this study, we designed and synthesized three FimB−Cec
conjugates, whose conjugation sites were selected without
sufficient information about the interaction between FimB and
the cognate receptor, FbsN.15 However, through a series of
MIC determination experiments, we clearly demonstrated that,
for all conjugates (18a−18c), FimB attachment could greatly
enhance the antimicrobial activity of the parent antibiotic via
facilitated cellular uptake through the activated FimB trans-
porter system. In addition, the activity enhancement was found
to be Acinetobacter-selective, although the efficacy against the
Acinetobacter clinical isolates awaits further evaluation.
Interestingly, although C-4-derivatized 18a exhibited the
highest activity, the activity difference among the three
conjugates was not as large as we initially predicted. To
further understand this observation, a rough molecular model
of the iron−FimB complex was developed considering the 1:1
binding stoichiometry26 as well as the preferred octahedral
geometry of the ferric ion. As shown in Figure S5 of the
Supporting Information, all conjugation sites used in this study
are located in the same hemisphere, reminiscent of the crystal
structure of the enterobactin−Fe(III) complex.30 This likely
suggests that the FimB−FbsN interaction primarily occurs on
the other side constituting the backbone architecture. Indeed,
this hypothesis is consistent with our previous finding that the
stereochemistry of the FimB backbone has a significant
influence on its siderophore activity.26
Notably, Miller and co-workers have reported a number of
successful siderophore−antibiotic conjugates whose side-
rophore structure featuring two catechols and one hydrox-
amate is similar to fimsbactin. These sideromycins, just like
compounds 18a−18c, exhibited selective antibiotic activities
against A. baumannii over other Gram-negative bacteria.31−33
Such selectivity was hypothesized to involve the exploitation of
the entry passage used by fimsbactin. In these cases, the
antibiotic molecule was conjugated to the hydroxamate
position, corresponding to the compound 18c structure.
Because compound 18a was more potent than compound
18c, it would be interesting to test whether the antimicrobial
activity of their sideromycins could be further enhanced by
antibiotic conjugation on one of the catechol motifs.
This study successfully demonstrated that FimB is an
effective delivery vehicle by invigorating a virtually inactive
antibiotic, cefaclor, against A. baumannii. This is the first
example of exploiting a natural siderophore of A. baumannii for
this purpose. To identify the optimal conjugate design, a semi-
shotgun strategy was employed, through which diverse
conjugation sites were investigated. In addition, the prepara-
tion of the conjugates could be streamlined by efficient late-
stage functionalization, particularly based on cross-coupling
reactions. The flexibility of the established synthetic route
would expedite further structural optimization, including the
linker variation as well as attachment of other antibiotics.
Supplemental figures, experimental procedures for
1
biological assays as well as chemical synthesis, H and
13C nuclear magnetic resonance (NMR) and high-
resolution mass spectrometry (HR-MS) spectra for all
new compounds, and supplemental references (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Hak Joong Kim − Department of Chemistry and Center for
ProteoGenomics Research, Korea University, Seoul 02841,
Republic of Korea; orcid.org/0000-0002-3213-2230;
Email: hakkim@korea.ac.kr
Author
Do Young Kim − Department of Chemistry and Center for
ProteoGenomics Research, Korea University, Seoul 02841,
Republic of Korea
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01786
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by grants from the Korea Centers for
Disease Control and Prevention, Ministry of Health and
Welfare, Republic of Korea (2019-ER5401-00), the National
R e s e a r c h F o u n d a t i o n o f K o r e a ( N R F -
2018R1D1A1A02086039), and the Korea Basic Science
Institute (KBSI) National Research Facilities & Equipment
Center (NFEC), funded by the Korean government (Ministry
of Education) (2019R1A6C1010028).
REFERENCES
■
(1) Wilson, B. R.; Bogdan, A. R.; Miyazawa, M.; Hashimoto, K.;
Tsuji, Y. Siderophores in Iron Metabolism: From Mechanism to
Therapy Potential. Trends Mol. Med. 2016, 22, 1077−1090.
(2) Górska, A.; Sloderbach, A.; Marszałł, M. P. Siderophore−Drug
Complexes: Potential Medicinal Applications of the ‘Trojan Horse’
Strategy. Trends Pharmacol. Sci. 2014, 35, 442−449.
(3) Ji, C.; Juárez-Hernández, R. E.; Miller, M. J. Exploiting Bacterial
Iron Acquisition: Siderophore Conjugates. Future Med. Chem. 2012,
4, 297−313.
(4) Hider, R. C.; Kong, X. Chemistry and Biology of Siderophores.
Nat. Prod. Rep. 2010, 27, 637−657.
(5) Miethke, M.; Marahiel, M. A. Siderophore-Based Iron
Acquisition and Pathogen Control. Microbiol. Mol. Biol. Rev. 2007,
71, 413−451.
(6) Blair, J. M. A.; Webber, M. A.; Baylay, A. J.; Ogbolu, D. O.;
Piddock, L. J. V. Molecular Mechanisms of Antibiotic Resistance. Nat.
Rev. Microbiol. 2015, 13, 42−51.
5259
https://doi.org/10.1021/acs.orglett.1c01786
Org. Lett. 2021, 23, 5256−5260

Organic Letters
pubs.acs.org/OrgLett
Letter
(7) Zgurskaya, H. I.; López, C. A.; Gnanakaran, S. Permeability
Barrier of Gram-Negative Cell Envelopes and Approaches To Bypass
It. ACS Infect. Dis. 2015, 1, 512−522.
(25) Ho, Y.-H.; Ho, S.-Y.; Hsu, C.-C.; Shie, J.-J.; Wang, T.-S. A.
Utilizing an Iron(III)-Chelation Masking Strategy to Prepare Mono-
and Bis-Functionalized Aerobactin Analogues for Targeting Patho-
genic Bacteria. Chem. Commun. 2017, 53, 9265−9268.
(26) Kim, S.; Lee, H.; Song, W. Y.; Kim, H. J. Total Syntheses of
Fimsbactin A and B and Their Stereoisomers to Probe the
Stereoselectivity of the Fimsbactin Uptake Machinery in Acinetobacter
baumannii. Org. Lett. 2020, 22, 2806−2810.
(27) Ree, H.; Kim, J.; Song, W. Y.; Lee, J. E.; Kim, H. J. Total
Syntheses and Evaluation of the Siderophore Functions of Fimsbactin
B and Its Analogs. Bull. Korean Chem. Soc. 2015, 36, 1520−1523.
(28) Joshua, A. V.; Sharma, S. K.; Abrams, D. N. New Short
Synthesis of (5)-2,3-Dimethoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-
iodobenzamide: Dopamine D2 Receptor. Synth. Commun. 2008, 38,
434−440.
(29) Tibrewal, N.; Elliott, G. I. Design, Synthesis and Evaluation of
AdSS Bisubstrate Inhibitors. ChemMedChem 2020, 15, 2269−2272.
(30) Johnstone, T. C.; Nolan, E. M. Determination of the Molecular
Structures of Ferric Enterobactin and Ferric Enantioenterobactin
Using Racemic Crystallography. J. Am. Chem. Soc. 2017, 139, 15245−
15250.
(31) Wencewicz, T. A.; Miller, M. J. Biscatecholate−Monohydrox-
amate Mixed Ligand Siderophore−Carbacephalosporin Conjugates
Are Selective Sideromycin Antibiotics That Target Acinetobacter
baumannii. J. Med. Chem. 2013, 56, 4044−4052.
(32) Ghosh, M.; Miller, P. A.; Möllmann, U.; Claypool, W. D.;
Schroeder, V. A.; Wolter, W. R.; Suckow, M.; Yu, H.; Li, S.; Huang,
W.; Zajicek, J.; Miller, M. J. Targeted Antibiotic Delivery: Selective
Siderophore Conjugation with Daptomycin Confers Potent Activity
against Multidrug Resistant Acinetobacter baumannii Both in Vitro and
in Vivo. J. Med. Chem. 2017, 60, 4577−4583.
(33) Liu, R.; Miller, P. A.; Vakulenko, S. B.; Stewart, N. K.; Boggess,
W. C.; Miller, M. J. A Synthetic Dual Drug Sideromycin Induces
Gram-Negative Bacteria To Commit Suicide with a Gram-Positive
Antibiotic. J. Med. Chem. 2018, 61, 3845−3854.
(34) Moynié, L.; Luscher, A.; Rolo, D.; Pletzer, D.; Tortajada, A.;
Weingart, H.; Braun, Y.; Page, M. G. P.; Naismith, J. H.; Köhler, T.
Structure and Function of the PiuA and PirA Siderophore-Drug
Receptors from Pseudomonas aeruginosa and Acinetobacter baumannii.
Antimicrob. Agents Chemother. 2017, 61, e02531−16.
(8) Vila, J.; Martí, S.; Sánchez-Céspedes, J. Porins, Efflux Pumps and
Multidrug Resistance in Acinetobacter baumannii. J. Antimicrob.
Chemother. 2007, 59, 1210−1215.
(9) Bonomo, R. A. Cefiderocol: A Novel Siderophore Cephalosporin
Defeating Carbapenem-Resistant Pathogens. Clin. Infect. Dis. 2019,
69, S519−S520.
(10) Wong, D.; Nielsen, T. B.; Bonomo, R. A.; Pantapalangkoor, P.;
Luna, B.; Spellberg, B. Clinical and Pathophysiological Overview of
Acinetobacter Infections: A Century of Challenges. Clin. Microbiol.
Rev. 2017, 30, 409−447.
(11) Peleg, A. Y.; Seifert, H.; Paterson, D. L. Acinetobacter
baumannii: Emergence of a Successful Pathogen. Clin. Microbiol.
Rev. 2008, 21, 538−582.
(12) Gordon, N. C.; Wareham, D. W. Multidrug-Resistant
Acinetobacter baumannii: Mechanisms of Virulence and Resistance.
Int. J. Antimicrob. Agents 2010, 35, 219−226.
(13) Yamamoto, S.; Okujo, N.; Sakakibara, Y. Isolation and
Structure Elucidation of Acinetobactin., a Novel Siderophore from
Acinetobacter baumannii. Arch. Microbiol. 1994, 162, 249−254.
(14) Wuest, W. M.; Sattely, E. S.; Walsh, C. T. Three Siderophores
from One Bacterial Enzymatic Assembly Line. J. Am. Chem. Soc. 2009,
131, 5056−5057.
(15) Proschak, A.; Lubuta, P.; Grun, P.; Löhr, F.; Wilharm, G.; De
̈
Berardinis, V.; Bode, H. B. Structure and Biosynthesis of Fimsbactins
A−F, Siderophores from Acinetobacter baumannii and Acinetobacter
baylyi. ChemBioChem 2013, 14, 633−638.
(16) Penwell, W. F.; DeGrace, N.; Tentarelli, S.; Gauthier, L.;
Gilbert, C. M.; Arivett, B. A.; Miller, A. A.; Durand-Reville, T. F.;
Joubran, C.; Actis, L. A. Discovery and Characterization of New
Hydroxamate Siderophores, Baumannoferrin A and B, Produced by
Acinetobacter baumannii. ChemBioChem 2015, 16, 1896−1904.
(17) Minnick, A. A.; McKee, J. A.; Dolence, E. K.; Miller, M. J. Iron
Transport-Mediated Antibacterial Activity of and Development of
Resistance to Hydroxamate and Catechol Siderophore-Carbacepha-
losporin Conjugates. Antimicrob. Agents Chemother. 1992, 36, 840−
850.
(18) Zheng, T.; Bullock, J. L.; Nolan, E. M. Siderophore-Mediated
Cargo Delivery to the Cytoplasm of Escherichia coli and Pseudomonas
aeruginosa: Syntheses of Monofunctionalized Enterobactin Scaffolds
and Evaluation of Enterobactin−Cargo Conjugate Uptake. J. Am.
Chem. Soc. 2012, 134, 18388−18400.
(19) Wencewicz, T. A.; Long, T. E.; Möllmann, U.; Miller, M. J.
Trihydroxamate Siderophore−Fluoroquinolone Conjugates Are
Selective Sideromycin Antibiotics That Target Staphylococcus aureus.
Bioconjugate Chem. 2013, 24, 473−486.
(20) Noël, S.; Gasser, V.; Pesset, B.; Hoegy, F.; Rognan, D.; Schalk,
I. J.; Mislin, G. L. A. Synthesis and Biological Properties of Conjugates
between Fluoroquinolones and a N3″-Functionalized Pyochelin. Org.
Biomol. Chem. 2011, 9, 8288−8300.
(21) Rivault, F.; Liébert, C.; Burger, A.; Hoegy, F.; Abdallah, M. A.;
Schalk, I. J.; Mislin, G. L. A. Synthesis of Pyochelin−Norfloxacin
Conjugates. Bioorg. Med. Chem. Lett. 2007, 17, 640−644.
(22) Miller, M. J.; Walz, A. J.; Zhu, H.; Wu, C.; Moraski, G.;
Möllmann, 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.
(23) Ghosh, M.; Lambert, L. J.; Huber, P. W.; Miller, M. J. Synthesis,
Bioactivity, and DNA-Cleaving Ability of Desferrioxamine B-Nalidixic
Acid and Anthraquinone Carboxylic Acid Conjugates. Bioorg. Med.
Chem. Lett. 1995, 5, 2337−2340.
(24) Hennard, C.; Truong, Q. C.; Desnottes, J.-F.; Paris, J.-M.;
Moreau, N. J.; Abdallah, M. A. Synthesis and Activities of Pyoverdin−
Quinolone Adducts: A Prospective Approach to a Specific Therapy
Against Pseudomonas aeruginosa. J. Med. Chem. 2001, 44, 2139−2151.
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