Sulfonium, an Underestimated Moiety for Structural Modification, Alters the Antibacterial Profile of Vancomycin Against Multidrug-Resistant Bacteria

Article abstract of DOI:10.1002/anie.201902210

In the antibiotics arsenal, vancomycin is a last resort for the treatment of intractable infections. However, this situation is under threat because of the increasing appearance of vancomycin-resistant bacteria (VRB). Herein, we report a series of novel v

Full text of DOI:10.1002/anie.201902210

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Accepted Article
Title: Sulfonium, an underestimated moiety for structural modification,
alters antibacterial profile of vancomycin against multidrug-
resistant bacteria
Authors: Dongliang Guan, Feifei Chen, Yunguang Qiu, Bofeng Jiang,
Likun Gong, Lefu Lan, and wei huang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201902210
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10.1002/anie.201902210
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COMMUNICATION
Sulfonium, an underestimated moiety for structural modification,
alters antibacterial profile of vancomycin against multidrug-
resistant bacteria
Dongliang Guan[a,b], Feifei Chen[a], Yunguang Qiu[a,b], Bofeng Jiang[a], Likun Gong[a], Lefu Lan[a,b]*, Wei
Huang[a,b]
*
9]
Abstract: In the antibiotics arsenal, vancomycin was no doubt the last
resort to treat the intractable infections clinically. However, this
situation is under grave menace because of the increasing
appearance of vancomycin-resistant bacteria (VRB). Herein, we
attachment
of
membrane
disruption
fragments[8c,
,
pyrophosphate-targeting designs[10], vancomycin core-structure
modification by total synthesis[9e, 11], etc. Recently, a combined
modification of lipophilic and cationic motifs on vancomycin has
been used to enhance the permeability towards bacterial
membrane, including vancomycin derivatives carrying C-terminal
lipophilic quaternary ammonium moieties from Halder group[9d]
and carrying lysine-rich lipo-peptides from Cooper group[9f]. The
concept of the lipo-cation modification is that the lipid penetrates
into the bilayer of bacterial cell membrane and the cation interacts
with the negative charge of phospholipids, resulting in membrane
destruction of bacteria[9][12]. Ammonium, a common moiety of
positive charge for chemical modification, is widely used in
structural optimization during drug discovery and development.
However, for glycopeptide antibiotics, it was reported that the
ammonium-based positive charge on vancomycin may lead to low
urinary clearance and high accumulation in liver and kidney[13]. In
the case of lipopeptide antibiotics such as polymyxin, it consists
of a multi-ammonium structure, which is the major cause of its
nephrotoxicity.[14]
reported
a series of novel vancomycin derivatives carrying a
sulfonium moiety, which was an underestimated modification in
previous studies and rarely reported in literature. The sulfonium-
vancomycin analogues exhibited enhanced antibacterial activity
against VRB both in vitro and in vivo potently. More interestingly,
sulfonium can alter the innate feature of vancomycin and tune its
antibacterial activity against Gram-negative bacteria. The mechanism
studies illustrated that sulfonium modification enhances the
interaction of vancomycin with bacteria cell membrane and disrupts
membrane integrity. In addition, in vivo pharmacokinetic profile,
stability, and toxicity of these derivatives demonstrated good
druggability of sulfonium modification. This work provides a promising
strategy for combating drug-resistant bacterial infection, and also
advances the knowledge on sulfonium derivatives for structural
optimization and drug development.
Multidrug-resistant bacterial infection has become
threatening disease for human health worldwide[1]. Among them,
resistant Gram-positive Enterococcus faecium and
a life-
Sulfonium, as a cationic moiety, is largely underestimated in
structural optimization for drug development and is rarely reported.
In fact, sulfonium occurs naturally in plants[15], animals[16], and
Staphylococcus aureus are listed as high priority for new
treatments in “ESKAPE pathogens” and in “the list of drug-
resistant bacteria” released by WHO recently[2]. Vancomycin was
awarded as “the last resort” against Gram-positive bacteria
especially for methicillin-resistant Staphylococcus aureus
(MRSA)[3-5]. However, after over 50-year clinic medication,
vancomycin-resistant bacteria including vancomycin resistant S.
aureus (VRSA) and Enterococci (VRE) have emerged and
become new challenges in anti-infective treatment[6]. To tackle the
bacterial resistance, various modification strategies have been
applied to novel vancomycin derivatives, such as lipophilic
also in therapeutic reagents such as adenosylmethionine[16, 17]
,
bleomycin[18], and modified-echinomycin[19]. In a comparison
study, alkylsulfonium compounds indicated less toxic than their
ammonium and phosphonium analogues[20]. On the other hand,
the stability property, pharmacokinetic profile, and safety
evaluation on sulfonium compounds is still ambiguous, which
limits its wide application in medicinal chemistry. Herein, for the
first time we designed and synthesized a series of sulfonium-
containing vancomycin analogues, which exhibited enhanced
antibacterial activities against drug-resistant MRSA, VISA, VRE,
and even certain Gram-negative bacteria. Furthermore, stability,
pharmacokinetic, and safety assays of these derivatives were
also investigated.
modification on vancosamine[7], ligand binding enhancement[8]
,
[a]
D. Guan, F. Chen, Y. Qiu, B. Jiang, Prof. Dr. L. Lan, Prof. Dr. W.
Huang
We designed a series of sulfonium-vancomycin derivatives by
assembly of sulfonium moiety on four peripheral positions of
vancomycin at resorcinol (5a-k), vancosamine (8a-g and 11a-d),
C-terminal (13a-g), and N-terminal (15a-b) respectively (Scheme
1, Scheme S1-S4). We employed a regioselective reaction
between an epoxide and a methylthio group to synthesize the
sulfonium as previous reported for methionine modification on
proteins[21]. The resulted beta-hydroxyl sulfonium indicated better
stability based on the energy computation (Table S8, Figure S6).
In a general procedure, a methylthio group was loaded onto these
four modification sites via Mannich reaction, reductive amination,
or amide condensation, followed by S-alkylation with various
CAS Key Laboratory of Receptor Research, CAS Center for
Excellence in Molecular Cell Science, Center for Biotherapeutics
Discovery Research
Shanghai Institute of Materia Medica, Chinese Academy of
Sciences
555 Zuchongzhi Road, Pudong, Shanghai, China 201203
E-mail: huangwei@simm.ac.cn
llan@simm.ac.cn
D. Guan, Y. Qiu, Prof. Dr. L. Lan, Prof. Dr. W. Huang
Department
[b]
University of Chinese Academy of Sciences
No.19A Yuquan Road, Beijing 100049, China
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201902210
Angewandte Chemie International Edition
COMMUNICATION
lipophilic epoxides to achieve corresponding lipo-sulfonium
derivatives. Beside single-site modification, we also prepared
dual-site derivatives including compounds 5h-k, (combined
modification of sulfonium on resorcinol and biphenyl on
vancosamine) and compounds 11a-d (combined modification of
sulfonium on vancosamine and extra sugar or phosphonate on
resorcinol or vancosamine rather than C-terminus or N-terminus
(5/8 vs 13/15); (2) dual-site modification (5h-k/11a-d) does not
show further advantage in enhanced activity compared with
single-site modified derivatives; (3) length of S-lipophilic chains
indicated importance in tuning of activity; For MSSA and VISA,
C6-C8 carbon chains (5d/8c/8d) showed better activity. For VRE
resorcinol). For comparison purpose, corresponding thioether (16, strains, longer chains of C10-C12 compounds (5d-f/8d-f)
17, Scheme S7) and ammonium (18, 19, Scheme S8) compounds
were synthesized as control groups to explore the unique features
of sulfonium moiety.
indicated the best activity with over 512 to 2048-fold enhanced
activity than vancomycin; (4) compared to thioether and
ammonium
derivatives
(16-19),
sulfonium
compounds
(5d/8c/13d) indicated better activity especially for VRE with up to
Then, we sought to investigate how sulfonium modification may
affect the in vitro and in vivo antibacterial efficacy,
pharmacokinetic profile, toxicity, and mechanism of action. Table
1 summarized the in vitro antibacterial activities of the optimal
analogues against various drug-resistant Gram-positive bacteria
including MSSA, VISA (MRSA), VRE strains (more details in
Table S1-S4). These data clearly demonstrated that lipo-
sulfonium modification strategy dramatically alters the
antibacterial profile of vancomycin with up to more than 2048-fold
enhanced activity against certain strains. The structure-activity
relationship (SAR) analysis revealed that: (1) the optimal
modification positions of sulfonium on vancomycin were
32-fold enhancement.
Furthermore, we chose 5d and 8c to test their activities against
49 strains of 8 types of clinically isolated Gram-positive bacteria,
including S. aureus, S. epidermidis, E. faecium, E. faecalis, and
S. Pneumoniae (Table S3). Overall, these two sulfonium
derivatives indicated excellent antibacterial activity (MIC 0.03-
0.06 ug/mL for most strains) compared with vancomycin (MIC 1-
2 ug/mL). Compare to Telavancin or Oritavancin, 5d and 8c also
demonstrated 2-32 fold enhanced activity against S. aureus, S.
epidermidis, and S. Pneumoniae, and comparable activity against
E. faecium and E. faecalis.
Scheme 1. Reagents and conditions: (i) HCHO, DIPEA, H2O:MeCN=1:1,-10˚С, 12h; (ii) AcOH, 37˚С, 24h; (iii) a, DIPEA, DMF, 50˚С, 1.5h; b, NaCNBH3, TFA,
MeOH, r.t, 1h; (iv) HCHO, DIPEA, H2O:MeCN=1:1, -10˚С, 12h; (v) HATU, DIPEA, DMSO:DMF=1:1, r.t., 2h; (vi) NaCNBH3, H2O: ACN: AcOH =2:2:1, r.t., 48h.
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COMMUNICATION
Table 1. In vitro Activities of Vancomycin Derivatives against MSSA, VISA and VRE*.
MIC(μg/mL)
Compound
MSSA[a]
≤0.0625
0.25
VISA[b]
VRE(VanA) [c]
VRE(VanM) [d]
VRE(VanB) [e]
5d
0.25
0.5
2
8
2
2
1
≤0.0625
≤0.0625
0.5
5e
5f
4
1
0.125
0.25
0.25
0.25
0.125
2
8c
≤0.0625
≤0.0625
0.5
0.25
0.125
2
2
1
8d
2
≤0.0625
0.25
0.25
8
8e
0.5
0.25
16
8
8f
4
2
13d
0.125
0.5
1
13e
1
4
8
15b
1
2
32
16
8
2
1
16
17
≤0.0625
≤0.0625
≤0.0625
0.5
0.5
0.25
0.5
2
8
32
8
≤0.0625
≤0.0625
16
18
16
16
˃128
8
8
19
2
Vancomycin
Telavancin
2
8
>128
8
>128
≤0.0625
0.25
2
*Strains used: [a] MSSA (Methicillin-susceptible S. aureus): Newman strain, ATCC 25904; [b] VISA
(vancomycin intermediate resistant S. aureus): Mu 50, a Healthcare associated MRSA isolated in
Japan; [c] VRE (VanA phenoype): Efm-HS-0649, Glycopeptide-resistant E.faecium, isolated in
China; [d] VRE (VanM phenoype): Efm-HS-08257, Glycopeptide-resistant E.faecium, isolated in
China; [e] VRE (VanB phenoype): Van B(R), Glycopeptide-resistant E.faecium.
Table 2. In vitro Antibacterial Activity against 5 Types of Gram-negative Bacteria*
MIC(μg/mL)
Compound
Eco[a]
8
Kpo[b]
˃16
Aba[c]
4-8
Pae[d]
˃16
Mca[e]
0.25-0.5
32-64
5f
Polymyxin B
Vancomycin[r]
0.06-1
˃100
2-4
0.06
˃100
0.25-0.5
˃100
˃100
resistant
*[a] Eco, E. coli, 5 strains; [b] Kpn, K. pneumoniae, 3 strains; [c] Aba, A. baumannii, 3 strains; [d]
Pae, P. aeruginosa, 4 strains; [e] Mca, M. catarrhalis, 2 strains; [r], date from literature report.
Lipo-ammonium complex in polymyxin[22] and vancomycin
derivatives[23] was reported with antibacterial activity against
Gram-negative bacteria by disrupting the outer membrane. To
investigate whether lipo-sulfonium moiety could achieve similar
effect, we examined their antibacterial activity against E. coli and
P. aeruginosa (Table S4). Compounds 5d-g indicated moderate
activity against E. coli. The optimal compound 5f was assessed
on its activity against 17 strains of 5 types of clinically isolated
Gram-negative bacteria, including E. coli, K. pneumoniae, A.
baumannii, P. aeruginosa, and M. catarrhalis (Table 2).
Interestingly, 5f exhibited moderate activity against E. coli and A.
baumannii, but very potent antibacterial effect against M.
catarrhalis with even 128-fold enhanced activity than polymyxin B.
These data clearly demonstrated that sulfonium modification
significantly alters the antibacterial profiles of vancomycin with
enhanced activity and a broader spectrum.
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10.1002/anie.201902210
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infection, much higher than those of vancomycin group (20%).
These results verified the enhanced antibacterial activity of
sulfonium modification strategy.
Sulfonium modification was rarely used in previous research that
could be partially due to the poor knowledge on druggable
properties of sulfonium derivatives. Here, we sought to
understand how sulfonium moiety affects pharmacokinetics,
toxicity, stability, and mechanism of action of vancomycin
derivatives. The in vivo pharmacokinetics of 5d were tested on
normal CD-1 mice, compared to 16 (thioether), 18 (ammonium),
and vancomycin (Fig. 2A and Table S5). Sulfonium 5d exhibited
similar properties as ammonium 18, with increased half-life and
AUC compared to vancomycin but reduced half-life compared to
thioether 16, that may alleviate the accumulation toxicity as
reported in other lipo-vancomycin derivatives[13]. The cytotoxicity
assay was performed on HK-2 cell line since nephrotoxicity is the
major safety concern of vancomycin-type antibiotics. The results
(Fig. 2B) implicated that sulfonium 5d was significantly less toxic
than its thioether and ammonium analogues 16, 18, and 19 at 50
and 100 μM. These data demonstrated that sulfonium moiety is a
good fragment for optimization of in vivo PK profile and toxicity.
Figure 1. In vivo lethal challenge assay of 5d on infected mice models. Survival
rates of mice (15 mice each group) infected by (panel A) USA400 MW2 (MRSA)
and (panel B) XN108 (VISA) were recorded after treatment with 5d or
vancomycin at a single dose of 7 mg/kg (A) or 14 mg/kg (B) via i.v. injection at
the first day of infection. Statistical significance determined by the log-rank
(Mantel-Cox) test: **p < 0.01, *** p < 0.001.
Figure 2. Panel A: Single-dose (5 mg/kg) concentration-versus-time
pharmacokinetic profiles of 5d, 16, 18, and vancomycin in CD-1 mice. The
abscissa shows the time and the ordinate shows the plasma drug concentration
(Conc.) (n=3 per group). Panel B: Cytotoxicity assays of compounds 5d, 16, 18,
19 on HK-2 cell line (human renal proximal tubule epithelial cells).
Thereafter, we investigated the stability of the sulfonium
derivatives. In an 8-day stability assay by incubation of 8c in a
phosphate buffer (pH 7.5) at 37 oC (Table S6), the compound
indicated excellent stability with an estimated half-life of 12.3 days.
In another experiment of the antibacterial assay in a solution
containing human serum albumin (HSA), the results implicated
that binding with plasma protein (like HSA) does not significantly
affect the MIC values of sulfonium 5d and 8c (Table S7).
The in vivo efficacy was tested via a lethal challenge assay of
mice infected with the MRSA strain USA400 MW2 or VISA strain
XN108 respectively. As shown in Fig. 1, the survival rates of the
5d group were 86.7% for USA400 infection and 80% for XN108
Figure 3. Elucidation on mechanism of action (MOA) of sulfonium-vancomycin derivatives against VRE. Panel A: cytoplasmic membrane permeability assay of
vancomycin analogues at 10 μg/mL; Panel B: cytoplasmic membrane depolarization assay of vancomycin analogues at 21.5 μg/mL; Panel C: schematic diagram
of proposed MOA for these novel sulfonium-vancomycin derivatives.
Nextly, to explore the mechanism of action (MOA) of these
sulfonium derivatives, we tested membrane disruptive potential of
compounds 5d, 8c, 13d, 15b and their thioether analogues 16
and 17 against VRE and MRSA (Fig. 3, S3-S5). Bacterial
cytoplasmic membrane permeabilization and depolarization, as
two types of mechanisms for disrupting membrane integrity, were
measured. In membrane permeability assay, all tested sulfonium
compounds exhibited better permeabilization than vancomycin
and its thioether derivatives (Fig. 3A, S3, S4). The
permeabilization of sulfonium compounds was concentration-
dependent and 5d indicated excellent activity even at
a
concentration as low as 5 ug/mL. In membrane depolarization
assay, sulfonium derivatives also demonstrated enhanced effect
on dissipating bacterial membrane potential at a higher level
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10.1002/anie.201902210
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COMMUNICATION
compared to vancomycin and thioethers (Fig. 3B and S5). Based
on these data, we proposed a possible MOA of lipo-sulfonium-
vancomycin derivatives as shown in Fig. 3C. As the vancomycin
skeleton approaches bacterial cell wall, sulfonium cationic ion
interacts with the negative charges on bacterial membrane while
the hydrophobic aliphatic tail inserts into the bilayer. The
enhanced interaction between lipo-sulfonium moiety and
membrane of vancomycin-resistant bacteria may result in
disruption of membrane integrity and cell lysis, thus causing
bacterial death.
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In summary, we present a new strategy of sulfonium modification
for vancomycin-based structure optimization, which alters the
antibacterial profile of vancomycin against multi-drug resistant
bacteria and demonstrates good druggable properties of
pharmacokinetics, stability, toxicity, and MOA. This strategy
represents a rational, effective, and promising design of sulfonium
derivatives which was underestimated in medicinal chemistry. In
a practical application, sulfonium-vancomycin compounds enable
disruption of bacterial membrane to tackle the crisis of drug-
resistant bacterial infection, including both Gram-positive and
Gram-negative bacteria resistant to vancomycin. The optimal PK
and safety property of sulfonium derivative also render it a
prospective candidate for further development.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (NNSFC, No. 21572244, 21877116),
National Science & Technology Major Project “Key New Drug
Creation and Manufacturing Program” of China (No.
2018ZX09711002-006), and the Youth Innovation Promotion
Association of CAS (No. 2017328). We thank Dr. Houchao Tao,
Dr. Fei Zhao in ShanghaiTech University and Dr. Jingjing Shi in
SIMM for their kind help in MS determination.
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Angew. Chem. 2003, 115, 752-789.
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10.1002/anie.201902210
Angewandte Chemie International Edition
COMMUNICATION
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COMMUNICATION
Sulfonium moiety was modified onto
vancomycin, which enhanced the
antibacterial activity against
Dongliang Guan, Feifei Chen, Yunguang
Qiu, Bofeng Jiang, Likun Gong, Lefu
Lan*, Wei Huang*
vancomycin-resistant bacteria in vitro
and in vivo potently. The further
evaluation including toxicity, stability,
PK and MOA demonstrated the good
druggability of these sulfonium
derivatives. This strategy is beneficial
for combating drug-resistant bacterial
infection, and also advances the
knowledge on sulfonium derivatives
for drug development.
Page No. – Page No.
Sulfonium, an underestimated moiety
for structural modification, alters
antibacterial profile of vancomycin
against multidrug-resistant bacteria
This article is protected by copyright. All rights reserved.