Expansion of antibacterial spectrum of muraymycins toward pseudomonas aeruginosa

Article abstract of DOI:10.1021/ml5000096

It is urgent to develop novel anti-Pseudomonas agents that should also be active against multidrug resistant P. aeruginosa. Expanding the antibacterial spectrum of muraymycins toward P. aeruginosa was investigated by the systematic structure-activity relationship study. It was revealed that two functional groups, a lipophilic side chain and a guanidino group, at the accessory moiety of muraymycins were important for the anti-Pseudomonas activity, and analogue 29 exhibited antibacterial activity against a range of P. aeruginosa strains with the minimum inhibitory concentration values of 4-8 μg/mL.

Full text of DOI:10.1021/ml5000096

Letter
pubs.acs.org/acsmedchemlett
Expansion of Antibacterial Spectrum of Muraymycins toward
Pseudomonas aeruginosa
Yusuke Takeoka,† Tetsuya Tanino,‡ Mitsuaki Sekiguchi,† Shuji Yonezawa,† Masahiro Sakagami,†
Fumiyo Takahashi,† Hiroko Togame,† Yoshikazu Tanaka,† Hiroshi Takemoto,† Satoshi Ichikawa,*,‡,§
and Akira Matsuda‡
†Shionogi Innovation Center for Drug Discovery, Shionogi & Co., LTD., Kita-21, Nishi-11 Kita-ku, Sapporo 001-0021, Japan
‡Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan
§Center for Research and Education on Drug Discovery, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan
S
* Supporting Information
ABSTRACT: It is urgent to develop novel anti-Pseudomonas
agents that should also be active against multidrug resistant P.
aeruginosa. Expanding the antibacterial spectrum of muraymy-
cins toward P. aeruginosa was investigated by the systematic
structure−activity relationship study. It was revealed that two
functional groups, a lipophilic side chain and a guanidino
group, at the accessory moiety of muraymycins were important
for the anti-Pseudomonas activity, and analogue 29 exhibited
antibacterial activity against a range of P. aeruginosa strains with the minimum inhibitory concentration values of 4−8 μg/mL.
KEYWORDS: Antibiotics, drug-resistance, MraY, muraymycin, peptidoglycan, anti-Pseudomonas
enerally, Gram-negative bacterial pathogens are less
Gsensitive to antibacterial drugs in comparison with
Gram-positive bacteria because they possess an outer
membrane, which acts as a permeability barrier. Among them,
Pseudomonas aeruginosa is a common nosocomial pathogen that
is intrinsically resistant to a variety of drugs currently used in
the clinic, and immuno-compromised patients are at greater
risk of infection. The increased rate of acquired multidrug
resistance in P. aeruginosa also complicates anti-Pseudomonas
chemotherapy. Consequently, it is urgent to develop novel anti-
Pseudomonas agents that should also be active against
multidrug resistant P. aeruginosa.1−3 In choosing novel
antibacterial agents, the target must be essential for their
growth, a mechanism of action of the agent should be different
from existing drugs. The initial lead compounds should also be
amenable to structural changes that allow for optimization of
the potency and efficacy.4−8 Muraymycins (MRYs) (Figure 1,
1), isolated from a culture broth of Streptomyces sp.,9,10 are
members of a class of naturally occurring 6′-N-alkyl-5′-β-O-
Figure 1. Structures and biological activity of muraymycin D2 and its
lipophilic analogue.
aminoribosyl-C-glycyluridine antibiotics.11 The MRYs having a
lipophilic side chain have been shown to exhibit excellent
antimicrobial activity against Gram-positive bacteria. The MRYs
These studies revealed that the impact of the lipophilic
substituent on antibacterial activity was very large, and the
lipophilic analogue 2 showed a potent antibacterial activity
against a range of Gram-positive bacteria including methicillin-
inhibit the formation of lipid II and peptidoglycan and are
inhibitors of phospho-MurNAc-pentapeptide transferase
(MraY), which is responsible for the formation of lipid I in
the peptidoglycan biosynthesis pathway.12−16 The enzymes
involved in the biosynthesis of peptidoglycan are essential for
bacterial life and represent important targets for antibacterial
chemotherapy. Recently, we have investigated the systematic
structure−activity relationship (SAR) study of the MRYs.17−19
Received: January 9, 2014
Accepted: March 6, 2014
Published: March 6, 2014
© 2014 American Chemical Society
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ACS Medicinal Chemistry Letters
Letter
selective inhibitors of MraY and are nontoxic to human liver
hepatocellular (HepG2) cells. Consequently, the MraY
inhibitors are promising leads for antibacterial agents active
against drug-resistant Gram-positive bacterial pathogens. The
MraY enzyme is also conserved among Gram-negative bacteria;
however, the natural MRYs are not effective to these Gram-
negative bacteria, presumably as a consequence of outer
membrane impermeability. Here we describe our efforts to
expand antibacterial spectrum of the MRYs toward P.
aeruginosa.
It is expected that chemical modification of our MRY
analogues 2−10 modulates outer membrane permeability of P.
aeruginosa and makes it possible to expand antibacterial activity
toward this pathogen. However, antibacterial evaluation of 2−
10 for P. aeruginosa has not been investigated yet. We initiated
this program by revisiting anti-Pseudomonas activity of 2−10.
In addition, simple acyl derivatives 11−19 were also planned to
evaluate (Figure 2). As shown in Scheme 1, these analogues
were easily obtained by the Cbz deprotection of 6′-N-
aminopropyl-5′-β-O-aminoribosyl-C-glycyluridine 20,15 acyla-
tion of the liberated amine, and global deprotection by aqueous
TFA over 3 steps.
First, the inhibitory activity of the analogues on the purified
MraY enzyme (Staphylococcus aureus) was examined by
fluorescence-based MraY assay20,21 using UDP-MurNAc-
dansylpentapeptide, where the formation of dansylated lipid I
was monitored by fluorescence enhancement (excitation at 355
nm and emission at 535 nm), and the results are summarized in
Table 1. As a result, most of the analogues exhibited strong
inhibitory activity with a nanomolar range of the IC50s. Anti-
Pseudomonas activity of 1−19 was next evaluated against a
range of P. aeruginosa strains.22 As expected, MRY D2 (1)
showed a very weak activity, and its lipophilic analogue 2 did
not show any activity. Analogues 7−12 exhibited a moderate
activity with the MIC values of 8−64 μg/mL. Analogue 9,
which possesses the guanidino and the amino functional
groups, was the most active among those tested (MIC values of
8−32 μg/mL). It is a great contrast that the analogues 3 and 4
also have guanidine groups but show no anti-Pseudomonas
activity. Since these analogues have the terminal carboxylic acid,
it would partially neutralize the positive charge of the guanidino
group. Newly synthesized analogues 13−19, which have an
aromatic ring at the accessory moiety, were inactive to a range
of P. aeruginosa strains. As a result, analogues possessing net
positive charges at the accessory moiety tend to have the
expanded antibacterial activity toward P. aeruginosa although
there are some exceptions.
Figure 2. Structures of muraymycin analogues.
Scheme 1. Synthesis of Acyl Analogues 11−19
A revisit of the antibacterial evaluation of muraymycin
analogues gave us a direction for a further molecular design for
expanding the antibacterial spectrum to P. aeruginosa. Thus,
necessity of a lipophilic side chain and a guanidino group at the
accessory moiety was implied to be important for the anti-
Pseudomonas activity from the SAR in Table 1. Therefore, we
planned to diversify the relative positions of these two
functional groups to the core aminoribosyluridine moiety in
order to optimize the orientation of the three moieties as
shown in Figure 3. For example, the lipophilic side chain and
the guanidino group were linked in a linear manner to give
analogue 21. Interconversion of the lipophilic side chain and
the guanidino group gave N-acyl-L-arginine analogues 23−26.
Analogues 3−19 contains L-pentadecylglycin residue, the
preparation of which required a number of steps. The
molecular design of 23−26 enables us to use a commercially
resistant Staphylococcus aureus (MRSA) and vancomycin-
resistant Enterococci (VRE).18 An accessory urea-dipeptide
moiety could also be simplified to a large extent, and the
truncated analogues 3−10 (Figure 2) retained the antibacterial
activity.19 Other biological properties of these analogues were
also investigated, and it was found that these analogues are
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ACS Medicinal Chemistry Letters
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Table 1. Screening of Muraymycin Analogues 1−19 as Anti-Pseudomonas Agents
a
MIC (μg/mL)
MraY IC50
(nM)
P. aeruginosa
PAO1
P. aeruginosa YY165
(ΔmexB)
P. aeruginosa ATCC
P. aeruginosa SR
P. aeruginosa ATCC
compound
25619
27156
27853
1
2.8
1.1
0.8
0.7
0.8
4.2
2.4
3.8
2.2
8.5
2.6
2.7
29.6
6.4
9.6
8.1
13.5
33.1
105
n.d.
>64
>64
>64
>64
>64
>64
>64
64
64
64
32
>64
>64
>64
>64
>64
>64
>64
64
2
>64
>64
>64
>64
>64
32
>64
>64
>64
>64
>64
64
>64
>64
>64
>64
>64
64
3
4
5
6
7
8
32
32
32
9
16
8
8
16
32
10
>64
>64
64
16
16
64
64
11
32
32
>64
64
>64
>64
>64
>64
>64
>64
>64
>64
>64
0.5
12
32
32
13
>64
>64
>64
>64
>64
>64
>64
0.5
>64
>64
>64
>64
64
>64
64
>64
>64
>64
>64
>64
>64
>64
0.031
14
15
64
16
64
17
64
18
>64
>64
0.25
64
19
>64
0.063
doripenem
a
MICs were determined by a microdilution broth method as recommended by the CLSI with cation-adjusted Mueller−Hinton broth (CA-MHB).
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 3. Synthesis of Branched Analogues 27−29
available L-Arg derivative and simple fatty acids. Analogue 27 is
a branched version of 26, where the guanidino group located in
Figure 3. Molecular design of analogues 21−29.
the accessory moiety is moved to the carboxylic acid at the 6′-
position of the uridine core structure. An interconversion of the
Scheme 2. Synthesis of Analogues 21−26
branching functional groups of 27 gave 28. Analogue 29 is a
hybrid-type of 26−28. Preparation of 21−26 is summarized in
Scheme 2. The key intermediate 3013−15 for the synthesis of
muraymycin D2 and its derivatives was used as a starting
material. The trichloroethoxycarbonyl (Troc) group was
removed by Zn in MeOH, and the liberated amine was
acylated with the corresponding carboxylic acids A−F (see
Supporting Information) by EDCI and HOBt in CH2Cl2.
Finally, the global deprotection by aqueous TFA successfully
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Table 2. MraY Inhibitory and Anti-Pseudomonas Activity of Analogues 21−29
a
MIC (μg/mL)
MraY IC50
(nM)
P. aeruginosa
P. aeruginosa YY165
(ΔmexB)
P. aeruginosa ATCC
P. aeruginosa SR
P. aeruginosa ATCC
compound
PAOl
25619
27156
27853
21
1491
97.3
225
9.8
>64
>64
>64
>64
32
>64
>64
>64
>64
16
>64
>64
>64
32
>64
>64
>64
>64
16
>64
>64
>64
>64
32
22
23
24
25
2.1
16
26
1.6
16
8
16
16
32
27
0.14
12.2
0.60
n.d.
16
8
8
8
16
28
32
16
16
16
16
29
4
4
8
8
8
doripenem
0.5
0.25
0.063
0.031
0.5
a
MICs were determined by a microdilution broth method as recommended by the CLSI with cation-adjusted Mueller−Hinton broth (CA-MHB).
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.
chain showed moderate activity. As was indicated by the first
screening shown in Table 1, two functional groups, a lipophilic
side chain and a guanidino group, at the accessory moiety were
important for the anti-Pseudomonas activity. The antibacterial
activity was also well-correlated to the length of the lipophilic
side chain. The branching analogues 27 and 28 have a similar
anti-Pseudomonas activity to 26. Finally, the hybrid-type
analogue 29 was the strongest activity among those tested in
this study. It is worthy to mention that P. aeruginosa YY165 is
slightly more sensitive to these analogues than other strains
tested in this study. P. aeruginosa YY165 is a deletion mutant of
MexB, which is an inner membrane transporter component of
the MexAB-OprM multidrug efflux system that confers
multidrug resistance. The sensitivity of analogues to P.
aeruginosa YY165 indicates that they could be a substrate of
the MexAB-OprM multidrug efflux system and excluded
outside the cell. The analogues 27 and 29 are almost
equipotent in terms of MraY inhibitory and anti-Pseudomonas
activities. Selective toxicity is a key concern in the chemo-
therapy for infectious diseases. Since the chemical structure of
27 and 29 contains the long lipophilic side chain and positively
charged guanidine functionality, it is suspected that the
analogues 27 and 29 act as detergents, which are sometimes
cytotoxic. Accordingly, their cytotoxic activity against human
hepatocellular liver carcinoma (HepG2) cells was then
evaluated. Analogue 27 showed cytotoxicity with an IC50
value of 4.5 μg/mL. Under these conditions, 29 exhibited
less cytotoxicity (IC50 34 μg/mL). With the observed higher
therapeutic index than 27, analogue 29 could be a lead for
further development as anti-Pseudomonas agent although
much improvement to reduce the toxicity is necessary. Finally,
the metabolic stability of 26, 27, and 29 was briefly evaluated by
treatment of these analogues with human or rat liver
microsome at 37 °C for 30 min and LC−MS/MS analysis of
remaining analogues (Table 3). Around 90% of each analogue
was unaffected by human liver microsomes, and these
analogues were revealed to be metabolically stable especially
to human liver microsomes.
Table 3. Metabolic Stability of Muraymycin Analogues 26,
27, and 29
a
26
27
29
b
human
rat
89.5%
81.1%
90.0%
80.7%
86.9%
69.8%
a
Rat and human liver microsomes were incubated at 37 °C in Tris-
HCl buffer (pH 7.4) containing 50 mM Tris-HCl, 150 mM KCl, 10
mM MgCl2, 1 mM β-NADPH, and 2 μM compounds. The protein
concentration was 0.5 mg/mL, and the final volume was 0.2 mL.
Incubations were terminated by the addition of 2-fold volume of ice-
cold acetonitrile/methanol 1:1, v/v) after 0 and 30 min of incubation.
Samples were centrifuged at 3000 rpm for 10 min prior to LC−MS/
MS analysis of the supernatants. Experiments were conducted in
b
duplicate. Percentage of the remaining material after treatment with
liver microsomes.
gave 21−26, respectively. Scheme 3 illustrates the preparation
of analogues 27−29. Another key intermediate carboxylic acid
3123,24 was coupled with Boc-protected 4-aminobutyl guanidine
G (see Supporting Information) by EDCI and HOBt to give 32
in 89% yield. After the Cbz protecting group was removed by
hydrogenolysis catalyzed by Pd/C, reductive alkylation of the
resulting amine with TrocHNCH2CH2CHO afforded 34 in
89% yield. Removal of the Troc group (Zn and MeOH),
acylation with palmitic acid (EDCI and HOBt), and
deprotection (80% aqueous TFA) provided 27 in 50% yield
over three steps. In a manner similar to the synthesis of 27, the
analogue 28 and the hybrid-type analogue 29 were prepared.
The MraY inhibitory activity of 21−29 was evaluated (Table
2). The linear analogues 21 and 22 reduced the inhibitory
activity. As for interconverted analogues 23−26, the length of
the lipophilic side chain is important for the MraY inhibitory
activity. Thus, the analogue 23 with the short side chain largely
reduced the activity with the IC50 value of 225 nM. Increasing
the length of the side chain resulted in an increase of the
inhibitory activity, and the length and the activity were well-
correlated. Analogue 26 with C16 side chain exhibited the IC50
value of 1.6 nM. Analogues 27 and 29 exhibited strong MraY
inhibitory activity (IC50 = 0.14 nM for 27 and 0.60 nM for 29,
respectively). The anti-Pseudomonas activity of this series of
the compounds was then evaluated (Table 2). The analogues
21 and 22 did not show any activity. The analogues 23 and 24,
which have the shorter lipophilic side chain, exhibited no
antibacterial activity, whereas 25 and 26 with the longer side
In conclusion, antibacterial spectrum of the MRYs toward P.
aeruginosa was investigated by the systematic SAR study of the
MRYs. It was revealed that two functional groups, a lipophilic
side chain and a guanidino group, at the accessory moiety of
MRYs were important for the anti-Pseudomonas activity. The
knowledge obtained from our SAR study of the MRYs would
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ACS Medicinal Chemistry Letters
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures for the synthesis and characterization
of synthesized compounds, fluorescence-based MraY assay,
antibacterial activity evaluation, and metabolic stability testing.
This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*(S.I.) E-mail: ichikawa@pharm.hokudai.ac.jp.
Funding
This research was supported by JSPS Grant-in-Aid for
Challenging Exploratory Research (Grant Number 22659020
to S.I.) and Scientific Research (B) (Grant Number 25293026
to S.I.).
■
Notes
(15) Bouhss, A.; Trunkfield, A. E.; Bugg, T. D.; Mengin-Lecreulx, D.
The biosynthesis of peptidoglycan lipid-linked intermediates. FEMS
Microbiol. Rev. 2008, 32, 208−33.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(16) Al-Dabbagh, B.; Henry, X.; El Ghachi, M.; Auger, G.; Blanot, D.;
Parquet, C.; Mengin-Lecreulx, D.; Bouhss, A. Active site mapping of
MraY, a member of the polyprenyl-phosphate N-acetylhexosamine 1-
phosphate transferase superfamily, catalyzing the first membrane step
of peptidoglycan biosynthesis. Biochemistry 2008, 47, 8919−8928.
(17) Tanino, T.; Ichikawa, S.; Shiro, M.; Matsuda, A. Total synthesis
of (−)-muraymycin D2 and its epimer. J. Org. Chem. 2010, 75, 1366−
1377.
■
We thank Ms. S. Oka and Ms. A. Tokumitsu (Center for
Instrumental Analysis, Hokkaido University) for measurement
of the mass spectra. We are also thankful for Ms. M. Okane and
Mr. K. Uotani (Shionogi Techno Advance Research Co., Ltd.)
for MIC measurement and Mr. K. Sekiguchi (Shionogi Co.,
Ltd.) for evaluating metabolic stability.
(18) Tanino, T.; Ichikawa, S.; Al-Dabbagh, B.; Bouhss, A.; Matsuda,
A. Synthesis and biological evaluation of muraymycin analogues as
potential anti-drug-resistant bacterial. ACS Med. Chem. Lett. 2010, 1,
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ABBREVIATIONS
■
Cbz, benzyloxycarbonyl; EDCI, 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide hydrochloride; HOBt, 1-
hydroxy-1H-benzotriazol; HepG2, human hepatocellular liver
carcinoma; IC50, 50% inhibitory concentration; MIC, minimum
inhibitory concentration; MRY, muraymycin; MraY, phospho-
MurNAc-pentapeptide transferase; MRSA, methicillin-resistant
Staphylococcus aureus; P. aeruginosa, Pseudomonas aeruginosa;
SAR, structure−activity relationship; TFA, trifluoroacetic acid;
Troc, trichloroethoxycarbonyl; C55−P, undecaprenyl−phos-
phate; VRE, vancomycin-resistant Enterococci
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