On-resin cyclization and antimicrobial activity of Laterocidin and its analogues

Article abstract of DOI:10.1016/j.tetlet.2009.11.007

Total synthesis of cyclodecapeptide antibiotics from Bacillus laterosporus, laterocidin and its analogues, was accomplished for the first time by solid-phase peptide synthesis followed by traceless on-resin cyclization of the linear precursors with protection of α-carboxyl group on the Asp residue by Dmab as a temporary blocking group for on-resin head-to-tail cyclization, in which the carboxyl group of side chain of Asp was linked to Rink resin. Single alanine substitution or Asn substitution (Asp¹⁰→Asn¹⁰) demonstrated improvements in antibacterial activity. Of note, d-Phe² and Pro⁴ play an important role in on-resin head-to-tail cyclization and exerting antibacterial activity of Laterocidin.

Full text of DOI:10.1016/j.tetlet.2009.11.007

Tetrahedron Letters 51 (2010) 1257–1261
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
On-resin cyclization and antimicrobial activity of Laterocidin and its analogues
*
Chuanguang Qin , Chunlan Xu, Ruijie Zhang, Weining Niu, Xiaoya Shang
Faculty of Life Science, Northwestern Polytechnical University, Xi’an 710072, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Total synthesis of cyclodecapeptide antibiotics from Bacillus laterosporus, laterocidin and its analogues,
Received 9 September 2009
Revised 23 October 2009
Accepted 3 November 2009
Available online 22 November 2009
was accomplished for the first time by solid-phase peptide synthesis followed by traceless on-resin cycli-
zation of the linear precursors with protection of a-carboxyl group on the Asp residue by Dmab as a tem-
porary blocking group for on-resin head-to-tail cyclization, in which the carboxyl group of side chain of
Asp was linked to Rink resin. Single alanine substitution or Asn substitution (Asp10?Asn10) demonstrated
improvements in antibacterial activity. Of note,
to-tail cyclization and exerting antibacterial activity of Laterocidin.
D
-Phe2 and Pro4 play an important role in on-resin head-
Keywords:
Laterocidin
Cyclopeptide
Antibiotics
Ó 2010 Elsevier Ltd. All rights reserved.
Solid-phase synthesis
The emergence of highly resistant microbe strains is increas-
ingly limiting the effectiveness of current therapeutic drugs such
as penicillins, vancomycin, cephalosporins, quinolones, tetracy-
clines and macrolides. Even now, resistance to these highly potent
drugs is being commonly seen in clinic.1 Making matters worse,
there is less motivation on the part of pharmaceutical companies
to spend billions on research and development of a novel antibiotic
when bacterial resistance is likely to occur rapidly.2
On the other hand, entirely new generations of drugs within a
class have been produced by making structural changes to existing
scaffolds, perhaps the most notable being the penicillins, cephalo-
sporins, quinolones, tetracyclines and macrolides.3 In light of this
method, we have selected Laterocidin, a natural product isolated
from the culture broth of Bacillus laterosporus, as a platform for this
study (Fig. 1). Polypeptide antimicrobials are not new to the field of
microbiology. Nature has long used linear and cyclic polypeptides
as natural defenses against competing or pathogenic bacteria.4
Natural cyclopeptide antibiotics such as gramicidins, polymyxins,
Valinomycin and daptomycin have been used extensively for top-
ical therapy with excellent results. Furthermore, cyclic peptide
derivatives such as cyclosporine, streptogramins, glycopeptides
and lipopeptides have been instrumental in controlling severe bac-
terial infections.
size/rigidity, hydrophobicity and amphipathicity.6 A collection of
similar studies have been conducted for cyclopeptide Tyrocidine
A and Gramicidin S. Formerly, we have demonstrated that by using
an alanine substitution screen, minor changes in the peptide com-
position of Tyrocidine A can lead to improvements in antibacterial
potency.7 Similarly, we can envisage that by making point substi-
tutions that alter the amphipathicity of the Laterocidin analogue,
the antibacterial activity may be systematically improved. Other
recent studies by Kohli et al. have demonstrated the utility of using
nonribosomal polypeptide synthetase (NRPS) technology for gen-
erating a privileged library of Tyrocidine A analogues that exhibit
moderate changes in antibacterial properties.8 The previous
Phe3
D-Phe2
OH
Pro4
N
H
N
Asn1
H2N
O
N
O
D-Tyr5
O
H
NH
O
O
NH2
HN
O
O
NH
HN
Asp10
HO
Recently, Tyrocidine A and Gramicidin S have received a great
deal of attention due to their highly desirable mechanism of action.
Both the compounds are known to form a b-type secondary struc-
ture leading to an amphipathic molecule.5 Studies have found that
bacteriocidal properties are influenced by several properties: rings
O
Leu6
HN
O
O
O
N
NH
H
Orn7
Leu9
O
Val8
Laterocidin
* Corresponding author. Tel.: +86 029 88491840; fax: +86 029 88460332.
E-mail addresses: qinchg@nwpu.edu.cn, qinchg2002@yahoo.com (C. Qin).
Figure 1. Structure of Laterocidin.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.007

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C. Qin et al. / Tetrahedron Letters 51 (2010) 1257–1261
success of these groups in modulating antibacterial properties by
using simple alanine screens and point amino acid substitutions
is highly encouraging and sets the stage for our work.
method for the generation of molecular diversity for enhancement
of the therapeutic index of the natural products.13 Recently, we
found that the biosynthetic precursors of tyrocidine A14 and gram-
icidin S15 adopt a pre-organized conformation, which is highly
favourable for specific head-to-tail cyclization. This led to a simpler
synthetic method for the natural occurring cyclic decapeptides
such as tyrocidines, streptocidins, gramicidin S and loloatins, using
acylsulfonamide safety-catch linker,16 without the need to protect
the reactive side chain functionalities in the cyclization product re-
lease step.
Laterocidin differs from tyrocidines and gramicidin S. Thus, the
convenient safety-catch linker method for Tyrocidine A can not be
directly employed to synthesize the novel cyclic decapeptide anti-
biotics. In this study, we would like to report the novel solid-phase
synthesis of Laterocidin via linking of the carboxyl group of side
With the favourable attributes of the cyclopeptides recognized,
we have set out to improve the collective understanding of their
structure–activity relationship using Laterocidin as our point of
reference. On the basis of similar sequence and structure, we antic-
ipated that the newly discovered Laterocidin adopts the same un-
ique antibiotic mechanism and may have bacterial specificity
different from other members in the family of amphipathic peptide
antibiotics. Thus, we embarked on their total synthesis to verify the
structures, to study their biological activities, and to develop a con-
venient method for analogue synthesis in an attempt to improve
their selectivity against bacteria.
Different methods have been developed for the synthesis of cyc-
lic peptides.9 Traditionally, C-terminal activation by N-hydroxy-
succinimide ester (ONSu) and azide of the linear peptide was
used in the synthesis of tyrocidines and gramicidins.10 More re-
cently, cyclization of peptides anchored on resin through the side
chain functionalities has been widely employed to afford the cyclic
peptides.11 Moreover, ‘safety-catch’ methods have been developed
for the synthesis of head-to-tail cyclic products.12 However, these
methods involve tedious side chain protection–deprotection
necessitated in the ring closure and are often hampered by the
poor cyclizing tendency of the linear peptide precursors. Further-
more, thioesterases are successfully applied in the synthesis of
tyrocidine A and analogues, which is suggested to be a general
chain of Aspartate to Rink resin with the protection of a-carboxyl
group of Aspartate by Dmab. In the experiment, we investigated
the effect of side chains of the self-cyclizing tendency of the scaf-
fold molecule. The constituent amino acids of the linear precursor
were sequentially substituted by alanine in a process called ‘ala-
nine-scanning’. D-Alanine was used to replace the D-Phenylalanine
in the parent molecule, since configuration of individual amino
acid had been shown to be important to the conformation of the
linear precursors.14 The substituted linear precursors were synthe-
sized and cyclized in parallel using IRORT’s AccuTag100 Combina-
torial Chemistry System,17 according to the method shown in
Scheme 1. Starting from 50 mg Rink resin (0.5 mmol/g,
O
H
O
H
N
Fmoc
HOBt, DIC, DMF
3h
N
ODmab
O
NH2
+
ODmab
NHFmoc
O
Rink resin
OH
H
N
O
Fmoc SPPS
20%Piperidine in DMF
15 min, 2 times
ODmab
O
NH2
H
N
O
H
N
O
OH
H2N
ODmab
H2N
NH
O
NH
O
2%N2H4 in DMF
3 min, 3 times
DPhe
Asp(OtBu)
Leu
Val
DPhe
Asp(OtBu)
Phe
Pro
Leu
Val
Phe
Pro
DTyr(tBu)-Leu-Orn(Boc)
DTyr(tBu)-Leu-Orn(Boc)
Asp(OtBu)-Leu-Val-Orn(Boc)-Leu-DTyr(tBu)-Pro-Phe-DPhe-Asp
PyBOP, HOBt, DIEA
NMP, 48 h
C
HN
O
3
2
1
6
5
4
10
9
7
Asp-Leu-V8al-Orn-Leu-DTyr-Pro-Phe-DPhe-Asn
TFA/PhOH/TIS/H2O
2.5 h
HN
C
O
d
Laterocidin = cyclo (-DLVOL YPFdFN-)
6 = cyclo (-NLVOLdAPFdFN-)
7 = cyclo (-NLVOAdYPFd FN-)
8 = cyclo (-NLVALdYPFdFN-)
9 = cyclo (-NLAOLdYPFdFN-)
d
1 = cyclo (-NLVOL YPFdFN-)
d
2 = cyclo (-NLVOL YPFdFA-)
d
3 = cyclo (-NLVOL YPFdAN-)
d
4 = cyclo (-NLVOLdYPA FN-)
10 = cyclo (-NAVOLdYPFdFN-)
11 = cyclo (-ALVOLdYPFdFN-)
5 = cyclo (-NLVOLdYAFdFN-)
Scheme 1. On-resin cyclization strategy for solid-phase synthesis of Laterocidin and its analogues (1–11).

C. Qin et al. / Tetrahedron Letters 51 (2010) 1257–1261
1259
100–200 mesh, 1% DVB) for each compound, the alanine-substi-
tuted products were obtained in good yields and characterized
after simplified purification, as summarized in Table 1. After so-
lid-phase synthesis, the linear precursor was cyclized on resin.
Subsequently, the cyclic product was simultaneously deprotected
and cut down from the resin with cocktail reagent. Finally, the tar-
get cyclopeptides were precipitated with cool ether and separated
with a centrifuge. After drying under vacuum, Laterocidin and its
analogues were obtained and characterized. The overall yield of
Laterocidin is 43.8%. In comparison with this, the yields of com-
pound 2 (Asn1?Ala1 and Asp10?Asn10) and compound 12 (As-
p10?Asn10), which were 46.5% and 43.1%, respectively, were
higher than those of other compounds. However, the yield of com-
pound 10 (Leu9?Ala9 and Asp10?Asn10), which was 17.6%, was
the lowest in comparison with those of other compounds. These
results indicated that Alanine residue of N- or C-terminal, and
different configuration of N- and C-terminal benefited to cycliza-
tion. Moreover, the hydrophobic residue such as alkyl group
(Leu) on N-terminal is adverse to cyclization. Turn tendency amino
acid (Pro) in the middle of linear peptide or trans-peptide bond
which is good for forming b-turn is better for cyclization.
MALDI-TOF Mass Spectrum of the cyclization product showed
only one molecular ion peak at 1224.5 (M+2 as isotope peak of
[M+H]+), consistent with the calculated mass of 1222.6 for Lateroc-
idin, indicating the absence of hydrolytic products or other trun-
cated peptide products. RP-HPLC analysis of the final products
without chromatographic purification showed that they are of high
purity (half >90%). Relatively overall low yield (17–25%) of the
products was probably due to the overestimation of the resin load-
ing value determined after attachment of the first amino acid
(Fmoc-Asp-ODmab). No free amine ground was found after the
cyclization reaction by Kaiser’s test. The data of the synthetic Late-
rocidin and analogues 1–11 indicated that they are the correct
head-to-tail cyclization products. These results show that the syn-
thetic scheme indeed affords the correct head-to-tail cyclic prod-
ucts without interference from the reactive side chain –NH2 and
Table 1
The cyclodecapeptide sequences of Laterocidin and its analogues
Entry
Cyclodecapeptide sequence
Calculated M+
Founda [M+H]+
Ret. timeb (min)
Purityc (%)
Yieldd (%)
Laterocidin
1
2
3
4
5
6
7
8
9
10
11
Cyclo(-DLVOLdYPFdFN-)
Cyclo(-NLVOLdYPFdFN-)
Cyclo(-NLVOLdYPFdFA-)
Cyclo(-NLVOLdYPFdAN-)
Cyclo(-NLVOLdYPAdFN-)
Cyclo(-NLVOLdYAFdFN-)
Cyclo(-NLVOLdAPFdFN-)
Cyclo(-NLVOAdYPFdFN-)
Cyclo(-NLVALdYPFdFN-)
Cyclo(-NLAOLdYPFdFN-)
Cyclo(-NAVOLdYPFdFN-)
Cyclo(-ALVOLdYPFdFN-)
1222.64
1221.65
1178.65
1145.62
1145.62
1195.64
1129.63
1179.61
1178.61
1193.62
1179.61
1178.65
1224.5
1222.6
1179.8
1146.7
1146.7
1196.7
1130.6
1180.6
1180.6
1194.7
1180.7
1180.6
27.0
29.3
30.1
27.4
25.4
26.0
29.7
25.2
30.4
27.3
26.2
26.9
70.0
90.7
82.9
72.3
71.1
87.5
93.2
83.1
91.2
91.0
91.6
95.0
43.8
20.9
46.5
35.1
40.4
21.7
24.6
24.5
40.3
24.9
17.6
43.1
a
The found values M+2 of entries Lacterocidin, 8 and 11 are the isotope of [M+H]+ as the main peak in MS.
Retention time, RP-HPLC analyses were performed with a Kromasil RP-C18 column (No. NC-2546-06251151, 5
b
lm, 250 ꢀ 4.6 mm i.d.) on Waters 2696 separation module
system equipped with a 996 photodiode array detector. Flow conditions were: 1.0 mL minꢁ1 flow rate, a linear gradient of 80–20% A in 25 min, 20–0%A in another 10 min,
washed with 100% B for 10 min and then calibrated at 80% A for 15 min. Solution A was 0.1% TFA in double-deionized H2O and solution B was 0.1% TFA in acetonitrile.
c
Purity was determined by HPLC analysis of the unpurified cyclization products after being precipitated and washed with cool ether.
Overall yields were calculated from the loading value of the resin after first amino acid attachment.
d
11
10
9
8
7
6
5
4
3
2
1
Laterocidin
10
15
20
25
30
35
Retention Time (min)
Figure 2. HPLC chromatograms of laterocidin and its synthetic analogues (1–11) purified through a reversed-phase semi-preparative column. Eluted products were
0
monitored at 220 nm, collected and freeze-dried. Purification was performed with a reversed-phase semi-preparative Kromasil C18 300 AÅ column (No. NC-3010-07182, 5 lm,
300 ꢀ 10 mm id) on Waters 2696 separation module system equipped with a 996 photodiode array detector. Flow conditions were: 2.0 mL minꢁ1 flow rate, a linear gradient
of 80–20% A in 25 min, 20–0% A in another 10 min, washed with 100% B for 10 min and then calibrated at 80% A for 15 min. Solution A was 0.1% TFA in double-deionized H2O
and solution B was 0.1% TFA in acetonitrile.

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C. Qin et al. / Tetrahedron Letters 51 (2010) 1257–1261
Table 2
MIC of the cyclodecapeptide Laterocidin and its analogues (l
g/mL)a
Cyclic decapeptide
Organism (strain)b
B. subtilis
S. aureus
L-MRSA
E. coli
P. aeruginosa
ESBLS E. coli
L-E. coli
Laterocidin
1
2
3
4
5
6
7
8
9
10
11
16
1
4
16
4
32
2
2
4
2
2
32
2
8
64
32
32
2
8
32
4
2
4
128
4
16
16
8
16
4
8
>256
64
128
64
64
32
256
256
>256
256
>256
256
>256
>256
>256
>256
>256
>256
128
>256
256
256
128
128
>256
32
32
>256
32
>256
64
64
64
64
128
16
16
>256
16
32
256
128
4
4
>256
>256
>256
>256
64
>256
2
8
256
A
Minimal inhibition concentration of synthetic cyclopeptides after purification by semi-preparative RP-HPLC and freeze-dry (the purity more than 98%, see Fig. 2), required
to completely inhibit bacterial growth.
b
Gram-positive bacterium: B. subtilis, Bacillus subtilis; S. aureus, Staphylococcus aureus; L-MRSA, Clinical Methicilllin Resistance Staphylococcus aureus; Gram-negative
bacterium: E. coli, Escherichia coli; P. aeruginosa, Pseudononas aeruginosa; ESBLs E. coli, Extended-Spectrum Beta-Lactamase-Producing Escherichia coli; L-E. coli: Clinical
Medicinal Resistance Escherichia coli.
–OH groups in the cyclization step, as expected. The side chains of
the Laterocidin scaffold have minimal effect on the strong ten-
dency of the linear precursors to self-cyclize, and they are replace-
able for the generation of molecular diversity to enhance the
natural product’s activity or evolve a new biological function.
In the experiment, we further examined the antibiotic activity
of the synthetic products purified by semi-preparative RP-HPLC
and freeze-dry (purity more than 98%, HPLC chromatogram see
Fig. 2) using a modified broth dilution method.6a,18 As shown in Ta-
ble 2, minimum inhibition concentration (MIC) of these products
showed that they are indeed potent antibiotics against gram-posi-
tive bacterium and gram-negative bacterium, with potency com-
parable to that of Laterocidin. In further analysis of the
antimicrobial activities of Laterocidin and its analogues, it was
found that they are modestly potent towards gram-positive bacte-
rium. Moreover, mutual replacement of Phenylalanine and Tyro-
sine had little effect on the antimicrobial activities of Laterocidin.
However, configuration of amino acids had been shown to be
important to the antimicrobial activities of the cyclodecapeptide,
Foundation for the Returned Overseas Chinese Scholars, State Per-
sonnel Ministry of China (2007) and the Fundamental Research
Foundation of Northwestern Polytechnical University (JC200824).
Supplementary data
Supplementary data (experimental procedure, Mass Spectrum of
Laterocidin and its analogues) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2009.11.007.
References and notes
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