Synthesis and biological evaluation of muraymycin analogues active against anti-drug-resistant bacteria

Article abstract of DOI:10.1021/ml100057z

Muraymycin analogues with a lipophilic substituent were synthesized using an Ugi four-component assemblage. This approach provides ready access to a range of analogues simply by altering the aldehyde component. The impact of the lipophilic substituent on the antibacterial activity was very large, and analogues 7b-e and 8b-e exhibited good activity against a range of Gram-positive bacterial pathogens including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. This study also showed that the accessory urea-dipeptide motif contributes to MraY inhibitory and antibacterial activity. The knowledge obtained from our structure-activity relationship study of muraymycins provides further direction toward the design of potent MraY inhibitors. This study has set the stage for the generation of novel antibacterial lead compounds based on muraymycins.

Full text of DOI:10.1021/ml100057z

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Synthesis and Biological Evaluation of Muraymycin
Analogues Active against Anti-Drug-Resistant Bacteria
Tetsuya Tanino,† Satoshi Ichikawa,*,† Bayan Al-Dabbagh,‡, Ahmed Bouhss,‡
Hiroshi Oyama,§ and Akira Matsuda*,†
†Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan, ‡Laboratoire des
ꢀ
ꢀ
Enveloppes Bacteriennes et Antibiotiques, Institut de Biochimie et Biophysique Moleculaire et Cellulaire, UMR 8619 CNRS,
§
ꢀ
^
Universite Paris-Sud, Bat. 430, Orsay F-91405, France, and Shionogi Innovation Center for Drug Discovery, Shionogi & Co.,
LTD., Kita-21, Nishi-11, Kita-ku, Sapporo 001-0021, Japan
ABSTRACT Muraymycin analogues with a lipophilic substituent were synthesized
using an Ugi four-component assemblage. This approach provides ready access to a
range of analogues simply by altering the aldehyde component. The impact of the
lipophilic substituent on the antibacterial activity was very large, and analogues 7b-e
and 8b-e exhibited good activity against a range of Gram-positive bacterial pathogens
including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enter-
ococcus faecium. This study also showed that the accessory urea-dipeptide motif
contributes to MraY inhibitory and antibacterial activity. The knowledge obtained from
our structure-activity relationship study of muraymycins provides further direction
toward the design of potent MraY inhibitors. This study has set the stage for the
generation of novel antibacterial “lead” compounds based on muraymycins.
KEYWORDS Antibiotics, drug resistance, MraY, muraymycin, peptidoglycan, Ugi
four-component reaction
he extensive use of antibiotics has raised a serious
global public health problem. Because bacterial patho-
gens inevitably develop resistance to every new drug
accomplished the first total synthesis of MRY D2 (7a) and its
epimer (8a),20 featuring the convergent assemblage of the
urea-dipeptide carboxylic acid 2, isovaleraldehyde (3a), 2,4-
dimethoxybenzylamine (4), and the isonitrile derivative of the
aminoribosyluridine 5 by an Ugi four-component reaction21
(U4CR) as shown in Scheme 1. Herein, we describe the synthe-
sis and biological evaluation of MRYanalogues associated with a
lipophilic side chain as an initial structure-activity relationship
(SAR) study of MRYs, and the MRY analogues that we discov-
ered were effective against drug-resistant bacterial pathogens.
First, the inhibitory activity of 7a on the purified MraY
enzyme (Bacillus subtilis) was examined by quantifying the
incorporation of MurNAc-[14C]pentapeptide by MraY from
UDP-MurNAc-[14C]pentapeptide into lipid I, the product of
MraY (Table 1).22 It turned out that it was a strong MraY
inhibitor with an IC50 value of 0.01 μM. Compound 8a, which
is the epimer of 7a at the R-position of the Leu residue,
exhibited good MraY inhibitory activity (IC50 = 0.09 μM)
albeit reduced by a factor of 9 as compared to that of 7a. The
antibacterial activity of 7a and 8a was then evaluated.23
However, no antibacterial activity was exhibited by these
compounds when subjected to a range of Gram-positive
bacteria up to 64 μg/mL (Table 2), despite the fact that they
did exhibit potent inhibitory activity against their target
T
launched in the clinic, the need for new antibiotics to coun-
teract drug-resistant bacteria such as methicillin-resistant
Staphylococcus aureus (MRSA) and vancomycin-resistant
Staphylococcus aureus (VRSA) is critical.1 In choosing novel
antibacterial agents to address this problem, several criteria
need to be considered as follows: The target must be
essential for growth, the agent must be different from exist-
ing drugs, and the initial “hit” scaffold must be amenable to
structural changes that allow for optimization of the potency
and efficacy to generate “lead” compounds.2-6
The muraymycins (MRYs) (Figure 1, 1), isolated from a
culture broth of Streptomyces species,7,8 are members of a class
of naturally occurring 60-N-alkyl-50-β-O-aminoribosyl-C-glycylur-
idine antibiotics.9,10 The MRYs that have a lipophilic side chain
have been shown to exhibit excellent antimicrobial activity
against Gram-positive bacteria. In particular, the efficacy of the
MRYs in S. aureus-infected mice represents a promising lead for
the development of new antibacterial agents. The MRYs inhibit
the formation of lipid II and peptidoglycan and are believed to
be inhibitors of the phospho-MurNAc-pentapeptide transferase
(MraY), which is responsible for the formation of lipid I in the
peptidoglycan biosynthesis pathway.11 -15 Because MraY is an
essential enzyme in bacteria,16 it is a potential target for the
development of general antibacterial agents. Because of these
promising biological properties, the MRYs have become intri-
guing, challenging synthetic targets.17-19 Recently, we have
Received Date: March 18, 2010
Accepted Date: May 26, 2010
Published on Web Date: June 02, 2010
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enzyme MraY. Because the lipid bilayer of the cytoplasmic
membrane is thought to be a common barrier in bacteria,
this observed membrane permeability; these compounds lack
the hydrophobic side chain found in MRY A and B classes
(Figure 1), which have good antibacterial activity. Although not
essential to MraY inhibition, the fatty acyl side chain attached to
Table 1. Inhibitory Activities of the Synthesized Compounds
against the MraY Enzymea
7a
8a
7b
8b
17
IC50 (μM)
0.01
0.09
0.33
0.74
5
a The activities of the compounds were tested against purified MraY
from B. subtitis.22 The assay was performed in a reaction mixture of 10 mL
containing, in final concentrations, 100 mM Tris-HCl, pH 7.5, 40 mM MgCl2,
1.1 mM C 55-P, 250 mM NaCl, 0.25 mM UDP-MurNAc-[14C]pentapeptide
(337 Bq), and 8.4 mM N-lauroyl sarcosine. The mixture was incubated for
30 min at 37 °C. The radiolabeled substrate UDP-MurNAc-pentapeptide
and reaction product (lipid I, product of MraY) were separated by TLC on
silica gel plates. The radioactive spots were located and quantified with a
radioactivity scanner. IC50 values were calculated with respect to a control
assay without the inhibitor. Data represent the mean of independent
triplicate determinations.
Figure 1. Structures of MRYs (1).
Scheme 1
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Table 2. Antibacterial Activity
S. aureus ATCC
MIC (ug/mL)a
S. aureus
SR3637 (MRSA)
E. faecalis
E. faecalis
E. faecium
ATCC 19434
E. faecium
SR7917 (VRE)
compound
29213 (MSSA)
ATCC 29212
SR7914 (VRE)
7a
>64
>64
2
>64
>64
4
>64
>64
4
>64
>64
4
>64
>64
4
>64
>64
2
8a
7b
8b
2
4
2
4
0.5
4
0.25
8
7c
4
4
4
16
16
64
64
8
8c
8
16
32
64
8
8
4
4
7d
16
64
4
16
32
8
16
4
32
8
8e
7e
4
4
8e
16
>64
1
16
>64
1
16
32
1
16
64
>64
4
8
17
64
0.5
64
>64
vancomycin
a MICs were determined by a microdilution broth method as recommended by the NCCLS with cation-adjusted Mueller-Hinton broth (CA-MHB).23
Serial 2-fold dilutions of each compound were made in appropriate broth, and the plates were inoculated with 5 ꢀ104 CFU of each strain in a volume of
0.1 mL. Plates were incubated at 35 °C for 20 h, and then, MICs were scored.
Scheme 2
the peptide moiety of MRYs is necessary for antibacterial acti-
vity. Because the β-acyloxyleucine moiety found in the MRY A
and B classes could be susceptible to β-elimination or hydrolysis
by enzymes such as esterases, these shortcomings would have
to be overcome. Therefore, we designed and synthesized ana-
logues, which were linked to a hydrophobic substituent on the
MRY core structure via a C-C bond, as chemically and bio-
logically stable isosteres of the MRYs. Our synthetic route to 7a
and 8aprovides readyaccess to a range ofanalogues containing
an unnatural amino acid simply by altering the aldehyde
component. Thus, 2,20 4, 5,20 and hexadecanal (3b) gave, via
the U4CR in EtOH, 6b containing a pentadecylglycine residue in
its structure in 37% yield as a 1:1 mixture of diastereomers.
Deprotection of 6b was achieved by a two-step sequence [Zn,
1 M aqueous NaH2PO4, tetrahydrofuran (THF), then 80%
aqueous TFA] to afford the hydrophobic analogue 7b and its
diastereomer 8b, which were easily separated by reverse-phase
high-performance liquid chromatography (HPLC). The newly
formed stereogenic center at the pentadecylglycine residue of
each diastereomer was determined by conventional amino
acid analysis24 by using L- or D-pentadecylglycine as the refer-
ence compound (see the Supporting Information, Scheme S1).
The inhibitory effect of 7b and 8b on purified MraYactivity was
then evaluated (Table 1). The lipophilic analogues 7b and 8b
were found to be weaker inhibitors of MraY than 7a but still
potent (IC50 = 0.33 and 0.74 μM, respectively). Introducing the
long lipophilic side chain was still acceptable for MraY inhibi-
tion. The nature of the lipophilic side chain could influence the
antibacterial activity by modulating the membrane permeabil-
ity or the affinity to the target enzyme MraY. Therefore, ana-
logues incorporating a biphenyl moiety at the end (7c and 8c),
in the middle (7d and 8d), andat the junction(7e and 8e) of the
lipophilic moiety were also designed and synthesized. The
corresponding aldehydes, precursors for the U4CR assemblage,
were prepared as shown in Scheme 2. Cross-metathesis of
4-vinylbiphenyl (9) and 7-octen-1-ol in the presence of Grubbs
second generation catalyst25 (77% yield) was followed by cata-
lytic hydrogenation to give the saturated biphenylalcohol 10
(quant.). The primary alcohol was oxidized to give the alde-
hyde 3c. On the other hand, the aldehyde 1126 was bis-
homologated by the Horner-Wadsworth-Emmons reaction
to give the corresponding R,β-unsaturated ester, which was
reduced by catalytic hydrogenation to afford the saturated ester
12 in 82% yield over two steps. The ethyl ester was reduced
with DIBAL to give the aldehyde 3d in quantitative yield. The
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Scheme 3
32-64 μg/mL, although 17 possessed a hydrophobic substitu-
ent (Table 2). These results clearly show that the urea-dipeptide
accessory motif is also a contributing factor in the interaction
with MraY to result in strong antibacterial inhibitory activity. In
addition to and apart from the binding pocket interacting with
the 50-O-aminoribosyl-50-C-glycyluridine moiety, it is noteworthy
that there would be an additional binding site in MraY, which
recognizes the accessory urea-dipeptide motif.
In summary, MRY analogues with a lipophilic substituent
were synthesized by U4CR, which enabled us easily to
prepare MRY analogues containing unnatural amino acids.
The impact of the lipophilic substituent on the antibacterial
activity was very large, and analogues 7b-e and 8b-e
exhibited good activity against a range of Gram-positive
bacterial pathogens, including MRSA and VRE. This study
also indicated that the accessory urea-dipeptide motif con-
tributes to MraY inhibitory and antibacterial activity. The
knowledge obtained from our SAR study of MRYs would
provide further direction toward the design of potent MraY
inhibitors. Because MRYs possess relatively high molecular
weight and polarity, these structural features are in good
agreement with the property space characteristics of anti-
bacterial agents.30-33 This initial study has set the stage for
the generation of novel antibacterial “lead” compounds
based on MRYs and is currently being expanded.
last aldehyde 3e27 was prepared from the carboxylic acid 13 by
reduction of the acid with BH3 THF (95% yield) followed by
3
oxidation with MnO2 (quant.). With these aldehyde units in
hand, we have synthesized the analogues 7c-e and 8c-e via
the U4CR followed by global deprotection in a manner similar
to the preparation of 7b and 8b as shown in Scheme 1.28
The antibacterial activity of this series of compounds
was evaluated, and the results are summarized in Table 2.
The impact of the lipophilic substituent on the antibacterial
activity was very good, and both 7b and 8b exhibited good
activity against a range of Gram-positive bacterial patho-
gens including S. aureus SR3637 (MRSA) and Enterococcus
faecium SR7917 (VRE) with minimum inhibitory concentra-
tion (MIC) values of 0.25-4 μg/mL. The activity was compar-
able to that reported for MRY A and B classes.7,8 Thus, the
membrane permeability plays an important role in terms of
the antibacterial activity among this class of natural pro-
ducts. Of significance is the discovery of 8b with the “un-
natural” D-pentadecylglycine residue, which exhibited eight
times more potent antibacterial activity against E. faecium
SR7917 than that of 7b with the “natural” stereochemistry.
Overall, analogues with the “natural” stereochemistry were
slightly more potent than those with “unnatural” stereo-
chemistry against Staphylococci. Introducing the rigid bi-
phenyl group into the lipophilic side chain did not improve
antibacterial activity but rather reduced potency in the
case of 7d and 8d, which contain the biphenyl group in the
middle of the side chain. Further optimization of the lipo-
philic side chain therefore will be necessary. All of the
compounds prepared in this study exhibited no cytotoxicity
against human hepatoceller liver carcinoma (HepG2) cells
(IC50 > 100 μg/mL).
SUPPORTING INFORMATION AVAILABLE Full experimen-
tal procedures, compound purities by HPLC, and NMR data for all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author: *To whom correspondence should be
addressed. (S.I.) Tel: (þ81)11-706-3229. Fax: (þ81)11-706-4980. E-mail:
ichikawa@pharm.hokudai.ac.jp. (A.M.) Tel: (þ81)11-706-3228. Fax:
(þ81)11-706-4980. E-mail: matuda@pharm.hokudai.ac.jp.
Present Addresses: Department of Internal Medicine, Faculty
of Medicine and Health Sciences, United Arab Emirates University,
P.O. Box 17666, Al Ain, United Arab Emirates.
Author Contributions: T.T. contributed to the synthesis of
muraymycin analogues. B.A.-D. contributed to the MraY inhibitory
assay. S.I. was the PI of T.T., made significant writing and editing
contributions, and provided significant intellectual input. A.B. was
the PI of B.A.-D. and a collaborator of the Matsuda lab and provided
significant intellectual input. H.O. contributed to the cytotoxicity
assay. A.M. was the main PI of the entire project, was the overseeing
PI of T.T., S.I., and A.B., made significant writing and editing
contributions, and provided significant intellectual input.
MRYs share the accessory urea-dipeptide motif in addition to
the 50-O-aminoribosyl-50-C-glycyluridine moiety. To rapidly see
the impact of the accessory motif, a truncated analogue 17,
where the accessory motif was completely removed from 7b or
8b, was prepared from 1529 as shown in Scheme 3, and the
biological properties were compared. The truncated analogue
17 was found to be a much weaker MraY inhibitor with an IC50
value of 5 μM, which was a 6-12-fold reduction of the inhibitory
activity as compared to 7b and 8b (Ta ble 1 ). The antibacterial
activity of 17 was greatly decreased with MICs ranging from
Funding Sources: We acknowledge the CNRS UMR 8619
(support of B.A.-D. and A.B.).
ACKNOWLEDGMENT We thank Kouichi Uotani (Discovery
Research Laboratories, Shionogi & Co., Ltd.) for evaluating the
antibacterial activities of the synthesized analogues. We thank S.
Oka and A. Tokumitsu (Center for Instrumental Analysis, Hokkaido
University) for measurement of the mass spectra.
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