Precursor-Directed Diversification of Cyclic Tetrapeptidic Pseudoxylallemycins

Article abstract of DOI:10.1002/cbic.201800503

Cyclic peptides containing non-proteinogenic amino acids often exhibit a broad bioactivity spectrum and many have entered clinical trials with good prospects for drug development. We recently reported the discovery of six cyclic tetrapeptides, pseudoxylallemycins A–F (1–6), from a termite-associated Pseudoxylaria sp. X802. These compounds contain a rare O-homoallenyl-l-tyrosine moiety and show promising antimicrobial activity against the Gram-negative pathogenic bacterium Pseudomonas aeruginosa. To perform more detailed structure–activity studies, we pursued a precursor-directed diversification strategy. Herein, we report the purification, identification, and testing of 21 new pseudoxylallemycin derivatives.

Full text of DOI:10.1002/cbic.201800503

Accepted Article
Title: Precursor-directed Diversification of Cyclic Tetrapeptidic
Pseudoxylallemycins
Authors: Huijuan Guo, Alexander Schmidt, Philipp Stephan, Luka
Raguž, Daniel Daniel Braga, Marcel Kaiser, Hans-Martin
Dahse, Christiane Weigel, Gerald Lackner, and Christine
Beemelmanns
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10.1002/cbic.201800503
ChemBioChem
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Precursor-directed Diversification of Cyclic Tetrapeptidic
Pseudoxylallemycins
Huijuan Guo,[a] Alexander Schmidt,[a] Philipp Stephan,[a] Luka Raguž,[a] Daniel Braga,[a] Marcel
Kaiser,[c,d] Hans-Martin Dahse,[a] Christiane Weigel,[a] Gerald Lackner,[a,b] and Christine
Beemelmanns*[a]
Abstract: Cyclic peptides containing non-proteinogenic amino acids
often exhibit a broad bioactivity spectrum and many have entered
clinical trials with good prospects for drug development. We recently
reported the discovery of six cyclic tetrapeptides, the
A–F (1–6), from the stowaway fungus Pseudoxylaria sp. X802 of
fungus-growing termites (Figure 1).12,13
Although many of those NRPS-derived natural products exhibit
pharmacologically important activities, most compounds do not
possess desirable selectivity and pharmacokinetic properties. To
generate a broad substrate library for further biological testing,
different approaches including labour-intensive (semi)synthesis
or the re-engineering of NRPS variants have been applied. An
alternative approach is to make use of the intrinsic substrate
promiscuity of the underlying biosynthetic machinery, i.e.
precursor-directed biosynthesis. 144-16
pseudoxylallemycins A–F (1–6), from
Pseudoxylaria sp. X802. These compounds contain a rare O-
homoallenyl- -tyrosine moiety and showed promising antimicrobial
a
termite-associated
L
activity against the Gram-negative pathogenic bacterium
Pseudomonas aeruginosa. To perform more detailed structure-
activity studies, we pursued a precursor-directed diversification
strategy. Here, we report the purification, identification and testing of
21 new pseudoxylallemycin derivatives.
R1
O
O

O
aa
b
Introduction
A ( ): R1 = H R2 = H R3 = H
HN
N
N
1
O
B ( ): R1 = a R2 = a R3 = H
2
1
2
3
Nonribosomally synthesized peptides are amongst the most
widespread secondary metabolites in nature, with many
possessing bioactivities that can be exploited for therapeutic
applications.1 They are biosynthesized by large, modular
enzymes known as nonribosomal peptide synthetases (NRPS),2
which incorporate proteinogenic as well as many non-
O
3
C ( ): R = H R = a R = H
NH
RR3
1
2
3
4
D ( ): R = H R = a R = OH
E ( ): R1 = H R2 = b R3 = H
5
O
R2
F (6): R1 = a R2 = b R3 = H
Figure 1. Structures of pseudoxylallemyccins A‒F (1‒6).
proteinogenic amino acids.3
Many NRPS-derived natural
products are further enzymatically transformed by methylation,
acylation or glycosylation.1-4 The NRPS-based biosynthetic
machinery frequently reveals a certain degree of promiscuity
with respect to the accepted substrate scope resulting in the
formation of several derivatives of the same compound family.
The biosynthetic flexibility is proposed to provide a certain
degree of evolutionary advantage to the producing organism,1-4
as exemplified in the nonribosomal peptide synthetases (NRPS)
In light of our recent discovery, we became particularly
interested in the simultaneous formation of NRPS-derived
pseudoxylallemycin A (1), B (2) and C (3) (Figure 1), all three
exhibiting promising activity against Gram-negative pathogenic
bacteria. Pseudoxylallemycin A (1) is a symmetric tetrapeptide
containing two
tetrapeptide produced by X802. In contrast, derivative B (2)
consists of two O-homoallenyl- -Tyr-NMe- -Leu units and is only
L-Phe-NMe-L-Leu units and is the most dominant
L
L
based
bacterial
xenematide
diversification
strategy
(Xenorhabdus nematophila).5
produced in minor amounts, depending on the applied culture
conditions. Currently, we hypothesize that pseudoxylallemycins
are biosynthesized by an iterative NRPS containing one A-
domain specific for an aliphatic amino acid (Leu) and one A-
domain for aromatic amino acids (O-alkyl Tyr, Phe)
respectively.17 To understand the underlying amino acid
specificity in detail, we applied a precursor-directed biosynthesis
approach and tested the incorporation of differently substituted -
synthetic and commercial - amino acids into the tetrapeptidic
core structure.
Fungi are known producers of a broad array of structurally
diverse NRPS-derived natural products,6 which include
immunosuppressant cyclosporine from Tolypocladium inflatum,7
insecticidal
destruxin
from
Metarhizium
anisopliae,8
xyloallenolide A containing an aromatic allenic ether moiety from
a mangrove-associated Xylaria sp. 2508,9 as well as insecticidal
and antitumor bassianolide and beauvericin from Beauveria
bassiana.10,11 We recently reported the isolation of the
antibacterial tetracyclic peptides, named pseudoxylallemycins
The results of our precursor-directed biosynthesis experiments
indicate promiscuous NRPS machinery that is able to tolerate
more than ten different para-substituted aromatic amino acid
derivatives. Here, we report the isolation of 21 new
pseudoxylallemycin derivatives and the evaluation of their
antimicrobial, antiparasitic, and cytotoxicity activity.
[a]
Leibniz Institute for Natural Product Research and Infection Biology
– Hans Knöll Institute, Beutenbergstraße 11a, D-07745 Jena,
Germany, Christine.beemelmanns@hki-jena.de
[b]
[c]
Friedrich-Schiller University, Jena, Germany
Dr. Marcel Kaiser, Parasite Chemotherapy Unit, Swiss Tropical and
Public Health Institute, Socinstraße 57, 4002 Basel, Switzerland.
University of Basel, Petersplatz 1, 4003 Basel, Switzerland.
[d]
Supporting information for this article is given via a link at the end
of the document.
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10.1002/cbic.201800503
ChemBioChem
FULL PAPER
Results and Discussion
18 or 20 did not increase the production rates of allene-
containing pseudoxylallemycins B‒D (2‒4) (Figure 2). Instead,
the respective O-alkyne (23‒28) and O-alkenyl-L-tyrosine-
Precursor-directed Diversification
containing derivatives (29‒31) were isolated (Figure 3, and
Supporting Information). In contrast, supplementation of O-
homopropargyl tyrosine derivative 22 to the fermentation broth
of X802 significantly shifted the production rates towards the
unsymmetric allene-containing pseudoxylallemycin C (3) (Figure
For subsequent cultivation experiments we first synthesized O-
alkylated tyrosine derivatives 18–22 using a Williamson ether
protocol (Table 1).18 In short, Boc-
L-Tyr(OH)-OMe (7) was
deprotonated using Cs2CO3 and reacted with the respective
alkyl halides under reflux (Method A) or subjected to Mitsunobu
reaction conditions (Method B: 1-butinol, DIAD, PPh3, see
Supporting Information).19 Subsequent saponification followed
by acidic Boc-deprotection afforded the desired modified amino
acids (18–22) in overall moderate to good yields (30%–80%).
2). We then analysed if commercial para-substituted
L-
phenylalanine derivatives were incorporated into the tetrapeptide
backbone. Again, LC-MS analysis of culture extracts clearly
indicated the formation of 4-methyl-, 4-fluoro-, 4-chloro- and 4-
bromo-substituted pseudoxylallemycins (41‒52). However, no
incorporation of 4-nitro and 4-amino-phenylalanine into the
pseudoxylallemycin core structure was detectable by HRMS and
MS2, presumably as result of their electronic and cytotoxic
properties (lower growth rates, decreased biomass formation) at
higher millimolar concentrations.
Table 1. General synthetic procedure for preparation of
22).
L-tyrosinyl ethers (18–
entry
R
method[a]
product
Yield[b]
1
2
3
4
5
A
A
A
A
B
18
19
20
21
22
80%
83%
29%
69%
30%
[a] Method A: 1. Cs2CO3, R-X, reflux, 17 h; 2. 1 M LiOH, 0 oC to rt, 2.5 h; 3. 2 M
HCl, 0 oC to rt, 4.0 h. Method B: 1. DIAD, PPh3, 1-butinol, 0 oC, 30 min, then rt,
o/n; 2. 10% LiOH, THF, rt 30 min; 3. HCl in Et2O (4 M), 5 min, then HCl-gas, rt,
o/n; [b] isolated yield over 3 steps. Isolated intermediates 8–17 not shown.
In
a next step, we subjected the producing organism,
Pseudoxylaria sp. X802 (from now on named X802) to
cultivation conditions with and without the respective amino
acids. In short, strain X802 was grown for 3 weeks on potato-
dextrose-agar (PDA,6-well plates, 8 mL/well) containing 0.5 mM,
2.0 mM and 6.0 mM of the respective amino acid. Mycelium-
covered agar was extracted using MeOH and the methanolic
extracts were used to generate 10.0 mg/mL stock solutions for
comparative UHPLC-MS and MS2 analysis. Subsequently, MS2
data was analysed using molecular networking GNPS20 as
pseudoxylallemycins were clearly detectable in a characteristic
cluster arrangement (Figure S3).
As depicted Figure
incorporation of almost all tested O-alkyl, O-alkenyl and O-
alkyne- -tyrosine derivatives into the pseudoxylallemycin
backbone (23‒40), except sterically demanding O-tert-butyl
tyrosine and tyrosine itself (Supporting Information). In general,
pseudoxylallemycin A (1) (( -Phe-NMe- -Leu)2) was the most
abundant tetracyclic peptide, followed by the non-symmetric
pseudoxylallemycin C derivatives, in which one Phe residue is
replaced by the supplemented modified amino acid.
2 and Figure 3, we detected the
L
L-
Figure 2. Comparative LC-MS analysiis of culture extracts of strain X802
grown on solid media supplemented withh: a) solvent control DMSO/H2O; b) O-
L
L
homopropargyl-
L
-Tyr 22 (0.5 mM); c) O--homopropargyl-
-Tyr 22 (6.0 mM); e)) O-butyl- -Tyr 18 (0.5 mM); f) 4-Cl-
-Tyr (0.5 mM) (Y-axxis represents the relative intensity of
L-Tyr 22 (2.0 mM); d)
O-homopropargyl-
Phe (2.0 mM); g)
selected ion).
L
L
L-
L
Tyrosine derivatives 18, 20 and 22 (Table 1) are suspected to be
potential biosynthetic precursors of O-homoallenyl-L-Tyr
(Figure 3), the aromatic amino acid building block of
pseudoxylallemycins B‒D (2‒4). However, supplementation of
To test the promiscuity of the adenylation domain recognizing
aliphatic amino acids (Leu), we also supplemented growth
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10.1002/cbic.201800503
ChemBioChem
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medium with
L
-allylglycine,
-alanine (Table S2 and Figure S2). Subsequent
LC-MS analysis revealed only trace amounts of three possible
NMe- -valine derivatives (53‒55), but no incorporation of allyl or
L-propargylglycine, N-methyl-L-valine
and N-methyl-
L
L
propargylglycine was observed (Figure S2).
Isolation of pseudoxylallemycins G1–M3
To pursue the isolation and characterization of the most
prominently formed pseudoxylallemycin derivatives, we
performed a large-scale cultivation of X802 on PDA (5 L)
supplemented with 2 mM (or 0.5 mM) of the respective amino
acid precursors (O-methyl-, O-homoallyl- (20), O-propargyl- (21),
O-homopropargyl-L-tyrosine (22), 4-methyl-, 4-chloro- and 4-
bromo-phenylalanine). Again, X802 was cultivated for four
weeks until the agar was fully covered with mycelium. Agar
pieces were extracted twice using MeOH and concentrated
extracts were purified using pre-activated SPE-C18 cartridges.12
Subsequent Sephadex LH20 and semipreparative HPLC
purification resulted in the isolation of the corresponding
pseudoxylallemycins. Overall, 21 new derivatives obtained in
0.2–2.0 mg were fully characterized using comparative NMR
and ESI-HRMS/MS analysis (Figure 3, Supporting Information).
Bioactivities
Subsequently, we evaluated the cytotoxicity, antibacterial and
antiparasitic activity of our extended compound library. Similar to
previous reports,12 pseudoxylallemycins G1–M3 (23–31, 38–43,
and 47–52) showed moderate inhibitory activity against
Pseudomonas aeruginosa (MIC ~ 12.5 µg/mL) and towards
human umbilical vein endothelial cells HUVEC independently of
the introduced side chain modifications (GI50 9–15 µg/mL; Table
S33). As part of our bioactivity screening efforts
pseudoxylallemycins A‒C (1–3) were also subjected to
antiparasitic activity assays. Overall, pseudoxylallemycin B (2)
and C (3) showed antiparasitic, but due to their cytotoxic
properties, unselective activity against Trypanosoma brucei
rhodesiense (Table S34).
Chemical Modifications
The observed anti-microbial activity prompted us to synthesize
conjugates 57 and 58 containing a fluorophore tag to be able to
pursue
potential
mode
of
action
studies.
First,
pseudoxylallemycin G1–G2 (23–24) was subjected to click
chemistry conditions21 and coumarin fluorophore (57) to yield
derivatives 57 and 58 (Scheme 1). It is interesting to note that
compounds, such as 24 and 58, are bifunctional molecules that
are suitable for further in vivo modifications and target
identification.22
Figure 3. Newly isolated and characterizzed pseudoxylallemycins produced by
X802 using a precursor-directed biosynthhesis strategy.
R
R
O
O
4-azidocoumarin (56)
CuI, TBTA
HN
N
N
HN
N
N
O
O
MeOH/H2O
Conclusions
O
O
NH
NH
Pseudoxylallemycins are presumably of NRPS origin that
O
O
promiscuity.17
O
O
contains
two
A-domains
of
different
N
N
Supplementation of either O-modified tyrosine or para-
substituted phenylalanine derivatives to the fermentation broth of
X802 resulted in the incorporation of the unnatural amino acid
into the pseudoxylallemycin core structure. In all cases, the
simultaneous presence of new pseudoxylallemycin derivatives
N
23 R =
H
r.t., overnight
57
(65%)
O
r.t., overnight, then
MW, 50 °C, 1 h
24
•
58 (68%)
O
O
Scheme 1. Chemical modification of pseudoxylallemycins G1–G2 (23–24).
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dependency on pseudoxylallemycin formation. In total, 21 new
derivatives were isolated and characterized. Subsequent
bioactivity studies of isolated derivatives indicated structure-
independent inhibitory activities against the bacterial Gram-
negative pathogen Pseudomonas aeruginosa. Furthermore,
pseudoxylallemycins can be chemically functionalized using
click chemistry, modifications that can be used for future target
identification. Future work is now dedicated towards
understanding the biosynthetic pathway of both, the allenic
moiety and pseudoxylallemycins, in greater detail to enable
future engineering of this intriguing pathway.
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Experimental Section
Supplementary Information (SI) available: fermentation procedures;
isolation procedures, ESI-HRMS, 1H NMR, 13C NMR, and 2D NMR
spectra as well as chemical modifications.
Acknowledgements
We are grateful for financial support from the German Research
Foundation (DFG, CRC1127 ChemBioSys, BE 4799/2-1 and BE
4799/3-1) and the Daimler Benz foundation to CB. LR is
generously supported by the International Leibniz Research
School for Microbial and Biomolecular Interactions (ILRS). GL
and DB are also grateful for financial support from the Carl
Zeiss Foundation. We thank Michael Thomas Poulsen and Z. W.
de Beer for supporting our field work, Stefanie König and Oliver
Werz (FSU Jena) for initial assessment of anti-inflammatory
activities, Mrs. Heike Heinecke (HKI) for recording NMR spectra,
and Mrs. Andrea Perner (HKI) for HRMS measurements.
Keywords: natural products • non-ribosomal peptide synthase •
allenes • bioactivities • amino acids
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FULL PAPER
We report the identification of 21 new
pseudoxylallemycin derivatives, the
assessment of their antimicrobial
activity and first studies towards their
chemical derivatization.
Huijuan Guo, Alexander Schmidt, Philipp
Stephan, Luka Raguž, Daniel Braga,
Marcel Kaiser, Hans-Martin Dahse,
Christiane Weigel, Gerald Lackner, and
Christine Beemelmanns*
Page No. – Page No.
Precursor-directed Diversification of
Cyclic Tetrapeptidic
Pseudoxylallemycins
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