Total Syntheses of Fimsbactin A and B and Their Stereoisomers to Probe the Stereoselectivity of the Fimsbactin Uptake Machinery in Acinetobacter baumannii

Article abstract of DOI:10.1021/acs.orglett.0c00790

The stereoselective synthesis of fimsbactin A, a siderophore of the human pathogen Acinetobacter baumannii, was established. Based on this synthetic route, various fimsbactin stereoisomeric analogues were generated and tested for their iron delivery activity for A. baumannii. This investigation revealed that the fimsbactin uptake machinery in this bacterium was indeed highly stereoselective in substrate recognition.

Full text of DOI:10.1021/acs.orglett.0c00790

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Letter
Total Syntheses of Fimsbactin A and B and Their Stereoisomers to
Probe the Stereoselectivity of the Fimsbactin Uptake Machinery in
Acinetobacter baumannii
Soojeung Kim, Haeun Lee, Woon Young Song, and Hak Joong Kim*
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ABSTRACT: The stereoselective synthesis of fimsbactin A, a
siderophore of the human pathogen Acinetobacter baumannii, was
established. Based on this synthetic route, various fimsbactin
stereoisomeric analogues were generated and tested for their iron
delivery activity for A. baumannii. This investigation revealed that the
fimsbactin uptake machinery in this bacterium was indeed highly
stereoselective in substrate recognition.
Acinetobacter baumannii is a Gram-negative bacterium, and
infection by the drug-resistant variants of this pathogen has
been considered as one of the most serious threats to patients,
particularly those in the intensive care units, due to its high
mortality as well as the lack of effective antibiotics against it.1
The antibiotic resistance of A. baumannii develops via diverse
mechanisms. One of the unique characteristics of A. baumannii
drug resistance is a significant reduction in membrane
permeability, which is in part conferred by the decrease in
the number of porin proteins and alterations of the
lipopolysaccharide layer structure.2,3 Among various efforts
being pursued to overcome the drug permeability barrier of A.
baumannii, we and others have paid attention to development
of antibiotic delivery systems using siderophores as the carrier
vehicles.4−8
Siderophores are small molecule iron chelators that most
bacteria including A. baumannii rely on for assimilation of the
iron from the iron-deficient environments such as in the
human host.9 As successful acquisition of the iron over the
host system is essential for pathogenesis, the transporter
proteins responsible for siderophore uptake are upregulated at
the infection site.4
The siderophore-based drug delivery strategy exploits such
activated transporter systems for the intracellular delivery of an
antibiotic molecule conjugated to a siderophore. Since the
active siderophore uptake system is distinctive from conven-
tional drug uptake pathways based on passive diffusion, the
siderophore-based drug delivery system, often called a “Trojan
horse” approach, appears to be a promising strategy for
overcoming the drug permeability barrier of A. baumannii. In
fact, cefiderocol, a siderophore−cephalosporin conjugate
antibiotic,38 was recently approved by the U.S. Food and
Drug Administration (FDA) to treat the infection by Gram-
negative pathogens including antibiotic-resistant A. baumannii,
supporting the effectiveness of the siderophore-based antibiotic
delivery strategy.
Until now, three classes of siderophores, acinetobactins,10
fimsbactins (1a−1f, Figure 1),11 and baumannoferrins,12 were
identified from A. baumannii. Among them, acinetobactins
have been extensively characterized by us and other research
groups,13−20 but the other two siderophores have received
relatively less attention and, therefore, many questions
regarding the characteristics and functions of these side-
rophores remain unaddressed.
Fimsbactins are mixed-type siderophores in which two
catecholates and one hydroxamate are decorated on the
backbone composed of L-serine/threonine and putrescine to
serve as the iron-chelating motifs. The first total syntheses of
fimsbactin B (1b) as well as derivatives of fimsbactin D (1d)
and F (1f) were reported by our laboratory in the past.21
However, stereoselective preparation of fimsbactin A (1a), the
predominant fimsbactin factor in the A. baumannii culture
isolates, was elusive due to the occurrence of significant
epimerzation during its synthesis. In addition, functional
Received: March 2, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00790
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A

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The following mild saponification using potassium trimethylsi-
lanolate24 afforded the desired three west wing fragments (4a−
4c) in decent yields. The preparation of the east wing
fragments was based on the use of putrescine derivative 521
featuring the protected hydroxamate moiety (Scheme 1B).
This precursor was coupled with N-Fmoc, O-TBS-protected L-
or D-serine (6a, 6b) and chemoselective removal of Fmoc
groups using diethyl amine provided 7a and 7b, effectively.
With all necessary fragments in hand, we attempted to
synthesize fimsbactin A (1a, Scheme 2A). The first step toward
this goal was to combine 4a and 7a by formation of an amide
bond between them. Unfortunately, this step was found to
suffer from significant epimerization at C-10, giving a mixture
of 8a and 8b in ca. 3.75:1 ratio at best. While similar
epimerization was also observed in total syntheses of
transvalencin Z25 and anguibactin,17 extensive reagent screen-
ings could provide solutions to enable stereoselective amide
formations in those cases. Encouraged by these precedent
successes, a variety of different amide coupling agents were
tested with 4a and 7a, but unfortunately, none was found
selective enough to overcome the epimerization problem in
this case. Notwithstanding such disappointing results, we could
manage to separate 8a and 8b, and these intermediates were
individually employed in the following operations including
silyl deprotection, ester formation with 2, and global
deprotection based on palladium-catalyzed hydrogenolysis to
provide fimsbactin A (1a) as well as its C-10 epimer (epi-1a) in
pure forms.
To resolve the stereoselectivity problem encountered in the
initial attempt for synthesis of fimsbactin A, an alternative
synthetic strategy placing the oxazoline ring formation step
ahead of the problematic amide coupling reaction was
envisioned. Gratifyingly, this “post-cyclization” strategy worked
effectively and enabled stereoselective preparation of a key
intermediate 8a as shown in Scheme 2B. Specifically,
intermediate 3a was hydrolyzed, and the resulting acid was
coupled with a L-Ser-based east wing fragment 7a. While other
common coupling agents such as EDC, HATU, or PyBOP
gave low yields (<25%) in this transformation, the combina-
tion of DIC and Oxyma succeeded in providing the anticipated
product 9 as a single diastereomer in a decent yield.
Furthermore, dehydrative cyclization of 9 using MoO2(acac)2
as a catalyst was found to be highly stereoselective producing
the anticipated oxazoline product 8a in 63% yield with no hint
of epimerization. Interestingly, the use of picolinic acid
derivatives as ligands reported to be capable of improving
the yield of molybdenum oxide-catalyzed dehydrative cycliza-
tion26 was found rather detrimental herein. The intermediate
8a was then further manipulated following the reaction
sequence shown in Scheme 2A, and thus, the stereoselective
total synthesis of fimsbactin A could be successfully
established.
Figure 1. Structures of fimsbactins.
characterization of other fimsbactin factors was rudimentary at
best. Herein, we describe successful stereoselective synthesis of
fimsbactin A (1a) as well as evaluation of its siderophore
activity for A. baumannii in comparison with a minor isolate,
fimsbactin B (1b). Furthermore, preparation of a number of
fimsbactin stereoisomers allowed uncovering of the stereo-
chemical requirements for the recognition by the cognate
uptake machinery in A. baumannii.
The syntheses of fimsbactin A, fimsbactin B, and their
stereoisomers were formulated to include preparations of the
west wing fragments (4a−4c) and the east wing fragments (7a,
7b) followed by functional group derivatizations and
subsequent global deprotection as depicted in Scheme 1 and
2. First, for the preparation of the west wing fragments, o-xylyl-
protected 3,4-dihydroxyl benzoic acid (2) was coupled with L-
Ser-OMe, L-Thr-OMe, or D-Thr-OMe (Scheme 1A). The
resulting precursors (3a−3c) were then subjected to Ishihara’s
dehydrative cyclization catalyzed by a molybdenum oxide
catalyst22,23 to constitute the corresponding oxazoline moieties.
Scheme 1. Syntheses of the (A) West Wing (4a, 4b, and 4c)
and (B) East Wing (7a, 7b) Fragments
The synthesis of fimsbactin B (1b) could be seamlessly
accomplished by the analogous procedures employed for
fimsbactin A preparation (Scheme 2C). In this case, the amide
coupling steps between the west and east wing fragments were
not problematic because the methyl group at C-9 secured the
sterically stable trans geometry with respect to the substituent
at C-10 as observed in total synthesis of acinetobactin.27,28 In
an analogous manner, three stereoisomers of fimsbactin B
including a diastereomer with the C-10/C-9 stereochemistry
inverted (dia-1b), the C-14 epimer (epi-1b) as well as the
enantiomer (ent-1b) were prepared as depicted in Scheme 2C.
B
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a
Scheme 2. Syntheses of Fimsbactin A (1a), B (1b), and Their Stereoisomers (epi-1a, dia-1b, epi-1b, and ent-1b)
a
Unwedged bold and hashed lines were used to represent the relative configuration between C-9 and C-10 of 10a−d and fimsbactin B
stereoisomers.
With fimsbactin A (1a) and B (1b) in hand, the siderophore
functions of these compounds were evaluated by monitoring
their growth stimulating effects on A. baumannii ATCC 17978
cultured in the iron deficient media (Luria−Bertani media
supplemented with 275 μM 2,2′-bipyridyl or “DP”, an iron
chelator). As depicted in Figure 2A,B, iron-free apo-forms of
both 1a and 1b were very potent in stimulating the growth of
A. baumannii. Moreover, the activities between these two
compounds were comparable, indicating that the additional
methyl group at C-9, biosynthetically originated from L-
threonine, is neither detrimental nor beneficial for the
siderophore activity of fimsbactin B.
The stereoselectivity of siderophore uptake machineries has
been of interest with respect to gaining better understanding
on their specificity in siderophore recognition.29 A number of
investigations on this matter have revealed that the ability of a
siderophore uptake system to discriminate a specific stereo-
isomeric form varies case by case. For instance, the uptake
systems for vanchrobactin in Vibrio anguillarum30 and for
acinetobactin in Aeromonas salmonicida31 appeared to be
nonstereoselective. In contrast, various microorganisms includ-
ing Pseudomonas fluorescens, P. aeruginosa, Paracoccus deni-
trificans, and Escherichia coli were able to distinguish different
stereiosomers of the cognate siderophores, enantio-pyoche-
lin,32 pyochelin,32 parabactin,33 and enterobactin,34 respec-
tively.
than those of the corresponding natural fimsbactins.
Considering that all fimsbactin stereoisomers bind Fe(III) in
the 1:1 stoichiometry (Figure S1) with comparable affinity,
based on the EDTA competition assay (Figure S2), the growth
stimulation assay result clearly indicates that the fimsbactin
uptake machinery in A. baumannii ATCC 17978 is stereo-
selective. When two diastereomers of fimsbactin B, dia-1b and
epi-1b, were compared, the activity of the former was found
significantly higher than the latter. This observation suggests
that the fimsbactin uptake system is stricter on the stereo-
chemistry at C-14 than C-9/C-10 in the substrate selection.
The observation that the activity of epi-1a, the C-10 epimer of
fimsbactin A, was similar to that of dia-1b seemed consistent
with this proposition.
Very recently, Bohac et al. also reported successful growth
stimulation of A. baumannii ATCC 17978 by fimsbactin A
(1a), prepared by isolation from A. baumannii culture extracts
rather than via synthesis, in accordance with our observation.20
Interestingly, they observed weak growth stimulation of A.
baumannii ATCC 19606 upon treatment with low dosages of
1a. This is an unexpected result because this strain lacks genes
related to fimsbactin biosynthesis and utilization.35 To confirm
their observation, we also conducted a growth stimulation
assay using A. baumannii ATCC 19606 wildtype. As shown in
the graph on the left of Figure 2C, very weak growth
stimulation of this strain by treatment with up to 2.8 μM of
both apo-1a and apo-1b was detected. At high dosages,
however, the cellular growth was rather inhibited. In fact, such
phenomenon is not unprecedented, and the inhibition seems
to happen when the iron chelating effect of a siderophore
outcompetes its iron delivery activity, thereby limiting the
availability of mobile iron in the medium. Additionally, to
probe whether the iron delivery by fimsbactin A and B exploits
the outer membrane receptor, BauA, dedicated for acineto-
To probe whether the hitherto uncharacterized fimsbactin
uptake system in A. baumannii ATCC 17978 is capable of
discriminating the fimsbactin stereoisomers, the growth-
stimulating activities of epi-1a, dia-1b, epi-1b, and ent-1b
were evaluated as shown in Figure 2A,B. The most discernible
observation was a nearly complete lack of siderophore activity
of ent-1b. While other stereoisomers could stimulate the
growth of A. baumannii, their activities were markedly lower
C
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membrane permeability assay (PAMPA), a widely adopted
method providing an in vitro model for passive diffusion of a
certain molecule.36 Our PAMPA for iron-preloaded holo-
fimsbactin A (holo-1a) and B (holo-1b) was conducted in 100
mM pH 7 Tris·HCl buffer with 200 μM of each compound
using Corning Gentest PVDF precoated plates, and this
experiment led to determination of their permeability (Pe, 10−6
cm/s) to be 1.00 0.12 and 0.55 0.042, respectively. Since
highly permeable compounds typically have Pe of >1.5 × 10−6
cm/s,37 this result indicates that holo-fimsbactins would be
only marginally permeable. Considering multilayered architec-
ture of the A. baumannii cellular membrane, the observed low
Pe across the simple, artificial lipid bilayer structure of Corning
plates seems to suggest that at least passive diffusion is less
likely involved.
In summary, herein, successful stereoselective synthesis of
fimsbactin A was demonstrated, in which the epimerization-
prone amide coupling step could be circumvented by adopting
a post-cyclization strategy. Furthermore, fimsbactin B as well as
various diastereomers of fimsbactins were generated and used
to probe stereoselectivity of the fimsbactin uptake machinery
in A. baumannii ATCC 17978. The intracellular translocation
of fimsbactins was proposed to depend solely on a TonB-
dependent outer membrane receptor, FbsN, based on the
absence of either periplasmic siderophore binding protein or
inner membrane permease complex in the fimsbactin gene
cluster.11,20 Our growth stimulation assay showed that A.
baumannii ATCC 17978 was capable of discriminating
fimsbactin stereoisomers, in which the stereochemistry at C-
14 seemed to be a more significant determinant than C-9/C-
10. This observation well demonstrates highly stereoselective
nature of FbsN in its substrate recognition. Interestingly,
fimsbactins A and B were also capable of stimulating the
growth of an Acinetobacter strain lacking the fimsbactin cluster
such as A. baumannii ATCC 19606, albeit with very low
activity. It is still uncertain how the iron-bound fimsbactins
could be internalized inside this cell, while our PAMPA result
suggests that at least passive diffusion is less likely to be
involved.
Our current understanding on fimsbactin, one of the
siderophores for the human pathogen A. baumannii, has been
limited compared to another siderophore, acinetobactin, but
interests in its physiological functions, biochemical properties,
and potential therapeutic applicability are beginning to escalate
recently. In partiucular, it is worth noting the recent articles by
the Miller group demonstrating the capability of a fimsbactin-
like artificial siderophore to deliver antibiotic molecules, such
as daptomycin, inside the A. baumannii cells.7,8 This
observation strongly suggests that fimsbactin also has a
potential to serve as an effective antibiotic delivery vehicle
targeting A. baumannii. In this regard, a stereoselective method
for preparation of fimsbactin A as well as some characteristics
of the fimsbactin uptake machinery including its stereo-
selectivity presented herein could be a meaningful groundwork
for uncovering the identity as well as applicability of this
hitherto overshadowed siderophore molecule.
Figure 2. Growth promotion assay results. (A) The growth
promotion of A. baumannii ATCC 17978 wildtype (WT) by
treatment with different concentrations of fimsbactin A (1a), B
(1b), and their stereoisomers (epi-1a, dia-1b, epi-1b, and ent-1b). The
assays were conducted in 96-well microplates, in which 200 μL cell
solutions in iron-depleted LB media were cultured at 37 °C for 14 h
before measurement of the absorption at 600 nm (OD600) in
duplicate. (B) Time course of (A) at 2.8 μM of each fimsbactin factor.
(C) Growth promotion of A. baumannii ATCC 19606 WT and
ΔbauA mutant cultured in LB containing 175 μM DP at 37 °C by
treatment with fimsbactin A (1a) and B (1b). The OD600 values
were recorded after 36 h (n = 4; ns, not significant; *, p < 0.05; **, p
< 0.001).
bactin uptake, they were used to treat a mutant of A. baumannii
ATCC 19606 with bauA disrupted (ΔbauA). As depicted in
the graph on the right of Figure 2C, the growth stimulating
activities of fimsbactins for this strain were more evident than
for the wildtype, in which the concentration-dependent growth
stimulation increase was observed up to 8.3 μM. This result
suggests that A. baumannii ATCC 19606 relies more on
fimsbactins for iron acquisition when the acintobactin
utilization is incapacitated. The observed growth stimulation
of A. baumannii ATCC 19606 by fimsbactins in the absence of
both BauA and the fimsbactin uptake system leaves their iron
delivery pathway obscure. Bohac et al. proposed a possible
involvement of other TonB-dependent outer membrane
receptors present in A. baumannii ATCC 19606. Alternatively,
the internalization of iron-loaded fimsbactins via energy-
independent passive diffusion, either involving porin proteins
or not, is also conceivable.
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00790.
To experimentally address the possibility of passive diffusion
through the membrane, we conducted a parallel artificial
D
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Experimental procedures and characterization data
(PDF)
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AUTHOR INFORMATION
Corresponding Author
Ceccarelli, M.; Naismith, J. H. eLife 2018, 7, No. e42270.
(19) Bailey, D. C.; Bohac, T. J.; Shapiro, J. A.; Giblin, D. E.;
Wencewicz, T. A.; Gulick, A. M. Biochemistry 2018, 57, 6653.
(20) Bohac, T. J.; Fang, L.; Giblin, D. E.; Wencewicz, T. A. ACS
Chem. Biol. 2019, 14, 674.
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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
(21) Ree, H.; Kim, J.; Song, W. Y.; Lee, J. E.; Kim, H. J. Bull. Korean
Chem. Soc. 2015, 36, 1520.
(22) Sakakura, A.; Umemura, S.; Ishihara, K. Chem. Commun. 2008,
3561.
Authors
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2012, 75, 1037.
(26) Akasapu, S.; Hinds, A. B.; Powell, W. C.; Walczak, M. A. Chem.
Sci. 2019, 10, 1971.
Soojeung Kim − Department of Chemistry, Korea University,
Seoul 02841, Republic of Korea
Haeun Lee − Department of Chemistry, Korea University, Seoul
02841, Republic of Korea
Woon Young Song − Department of Chemistry, Korea
University, Seoul 02841, Republic of Korea
(27) Takeuchi, Y.; Ozaki, S.; Satoh, M.; Mimura, K.-I.; Hara, S.-I.;
Abe, H.; Nishioka, H.; Harayama, T. Chem. Pharm. Bull. 2010, 58,
1552.
Complete contact information is available at:
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(28) Kim, J.; Lee, J. E.; Ree, H.; Kim, H. J. Bull. Korean Chem. Soc.
2015, 36, 439.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(30) Soengas, R. G.; Larrosa, M.; Balado, M.; Rodríguez, J.; Lemos,
■
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M. L.; Jimenez, C. Org. Biomol. Chem. 2008, 6, 1278.
This work was supported by grants from 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 Korea government (Ministry
of Education) (2019R1A6C1010028). We also thank Prof.
Hugh Kim for his helpful advice on this manuscript.
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Lemos, M. L.; Jimenez, C. ACS Chem. Biol. 2017, 12, 479.
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