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Introduction
The emergence of bacterial resistance to different classes
of antibacterial agents, such as β-lactams, quinolones, and
macrolides, is an alarming problem that seriously affects
human health[1]. To combat this situation, numerous efforts
have been made in the development of new approaches to
treat bacterial infections, particularly for therapeutics with novel
mechanisms of action and little or no
cross-resistance[2_4]. As a result, new antibacterial agents against hospital-acquired
Gram-positive bacterial pathogens[5], especially against
methicillin-resistant Staphylococcus aureus (MRSA) and
vancomycin-resistant enterococci (VRE), have become the
center of attention in this highlighted research
field[6,7].
The guanidino group has long been recognized as a
ubiquitous moiety present in numerous therapeutic agents,
including cardiovascular, antihistamine, anti-inflammatory,
antidiabetic, antibacterial, antihypertensive, antiviral, and
antineoplastic drugs[8]. Many natural products also contain
guanidino moieties[9_12], and their strong cationic nature is
often associated with biological activities. Of particular
interest is the presence of guanidine in several peptidic antibiotics,
such as capreomycin[13],
viomycin[14],
tuberac-tinomycin[15], and
neomycin[16].
A class of guanidine-containing antibacterial agents that
targets a proteinase of microbial origin was identified as
competitive trypsin inhibitors in vitro and consists of various
aromatic esters of
trans-4-guanidinomethylcyclohexanecarboxylic acid
(GMCHA)[17_20]. For instance,
trans-4-guanidinomethyl cyclohexane carboxylic acid
(4-[4-{4-methylbenzyloxy carbonyl}phenyl] phenylester) (TG44), a
derivative of GMCHA[21], and 4-guanidinomethyl benzoic
acid (4-[4-{4-methylbenzyloxy carbonyl}phenyl]phenylester) (NE-2001; Figure 1) are both selective
synthetic antibiotic agents directed against Helicobacter
pylori (H pylori
)[22]. TG44, which is undergoing clinical
development, possesses rapid bactericidal activity and is
useful for eradicating not only the antibiotic-susceptible,
but also the antibiotic-resistant strains of H
pylori by monotherapy[21]. As a drug candidate, NE-2001 displays
superior anti-H pylori efficacy on clinical isolates either
resistant to metronidazole or resistant to both metronidazole
and clarithromycin[22].
The activity of NE-2001 as a selective antibacterial agent
against H pylori prompted us to conduct structural
modifications of this core molecule. In this report, we describe the
design, synthesis, and biological evaluation of novel
guanidine derivatives of aryl-4-guanidinomethylbenzoate (series
A) and N-aryl-4-guanidinomethylbenzamide (series B).
Twelve of these compounds demonstrated potent
antibacterial activities against Gram-positive microorganisms, such
as Staphylococcus aureus and Staphylococcus
epidermidis, but did not display or showed little or no
activity against Gram-negative Escherichia
coli, Pseudomonas aeruginosa, Salmonella
typhi, and so on. The results suggest that these compounds may have the potential to be
developed into narrow spectrum antibacterial agents to help
control the wide spreading of drug resistance.
Materials and methods
Chemistry General synthetic routes towards
aryl-4-guanidinomethylbenzoate (A1_24) and
N-aryl-4-guanidinomethylbenzamide derivatives (B1_20) are illustrated in
Figure 2[23]. The target
compound A6 was synthesized by condensation of
4-N-Boc-aminophenol and 4-guanidinomethylbenzoic acid (intermediate 1), followed by cleavage
of the Boc group under acidic
conditions[24]. The target compound B5 was synthesized by condensation of
4-benzyloxyaniline and intermediate 1, followed by cleavage of
the benzyl group catalyzed with
Pd-C[25]. Compounds A8_10 and B10_12 were prepared by condensation of the
intermediate 1 with intermediates 4-halo-4'-hydroxybenzophenone
or 4-amino-4'-halobenzophenone,
respectively[26,27]. Compounds A12_14 and B14_16 were prepared by condensation
of the intermediate 1 with intermediate
4-halo-4'-hydroxydiphenyl or 4-amino-4'-halodiphenyl,
respectively[28_30]. Substituted benzoyl guanidines (C1_4) and substituted phenyl
guanidines (D1_D4) were synthesized according to the
literature[31,32]. 4-Guanidinobenzoic acid and
4-guanidinophenylacetic acid were synthesized by the reaction of
aminoiminomethanesulfonic acid with 4-aminobenzoic acid and
4-aminophenylacetic acid,
respectively[33], followed by condensation with 4-phenylphenol using dicyclohexylcarbodiimide
(DCC) to give 4-phenylphenyl
4-guanidinobenzoate (E1) and 4-phenylphenyl 4-guanidinophenylacetate
(E2)[23]. All of the compounds were converted to their corresponding
hydrochloride salts for biological evaluation.
Antibacterial activity assay Antimicrobial activity was
determined by an agar dilution method according to the
Clinical and Laboratory Standard Institute (CLSI, formerly
National Committee for Clinical Laboratory Standards, NCCLS)
guidelines[34]. The test compounds were dissolved in DMSO
and diluted at 1:2 serially in distilled water to produce
various concentrations. The solutions were loaded onto plates
and blundered with quantitative Mueller-Hinton agar
medium. Inocula were prepared with overnight cultures and
inoculated with a multipoint inoculator (MIT-P, Sakuma,
Tokyo, Japan). Final inocula contained
1×104 colony-forming units (CFU)/spot. The plates were incubated at 35
oC for 18_24 h depending on the culture requirement. All the
bacteria strains used in this study were obtained from the
National Institute for the Control of Pharmaceutical and
Biological Products (Beijing, China). Meropenem
dissolved in distilled water (Sigma-Aldrich, St Louis, MO,
USA) was used as a positive control. Minimum inhibitory
concentration (MIC) values were determined as the lowest
concentration of the compound that inhibited visible growth.
Enzyme inhibition assay The oligopeptidase B (OpdB)
expression vector pET28a-OpdB was provided by Dr
Xue-yuan JIANG, Department of Biochemistry, Nanjing
University (Nanjing, China). Expression, purification, and the
enzymatic inhibition assay were carried out as described
previously[35] with minor modifications. The reaction volume was
reduced to 100 µL from 2 mL in which the amount of enzyme,
substrate, and test compounds decreased, but their
concentrations remained unchanged. Boc-Glu-Lys-Lys-MCA
(Peptide Institute, Osaka, Japan) was used as the substrate
for OpdB with a final concentration in the reaction mixture of
10 µmol/L. The liberated 4-methylcoumaryl-7-amide (MCA)
was measured fluorometrically with the EnVision 2101
multilabel reader (PerkinElmer, Boston, MA, USA). The
excitation and emission wavelengths were 355 and 460 nm,
respectively.
Purified OpdA (powder) was also supplied by Dr JIANG
and the assay procedure to measure OpdA activity was
similar to that in the literature[35], except that the reaction volume
was reduced to 100 µL. Enzymatic activities were determined
fluorometrically with a Shimadzu RF-5301
spectrofluorometer (Shimadzu Corporation, Kyoto, Japan).
Data analysis Data were analyzed using GraphPad
Prism software (San Diego, CA, USA).
Results
Growth inhibitory activities against Gram-positive and
negative bacteria We first observed moderate antibacterial
activities to certain Gram-positive bacteria, and very little
effect on some Gram-negative bacteria in 6 of the series A
and B compounds (Table 1). This phenomenon was
abolished when substituted benzoyl guanidines (C1-4) and
substituted phenyl guanidines (D1-4) were tested (MIC>256
µg/mL; Figure 3). Subsequent structural modifications were
directed towards a variety of substitutions on the phenyl
group, which led to the synthesis of 2 series of compounds,
aryl-4-guanidinomethylbenzoate derivatives (series A) and
N-aryl-4-guanidinomethylbenzamide derivatives (series B;
Table 2).
It was noted that many of the compounds (series A in
particular) were highly selective against most Gram-positive
microorganisms tested (eg Staphylococcus
aureus ATCC29213, Staphylococcus aureus
ATCC25923, Staphylococcus epidermidis ATCC12228), while their inhibitory
effects on a range of Gram-negative bacteria were minimal (eg
Escherichia coli ATCC25922, Pseudomonas
aeruginosa ATCC27853, Enterobacter
cloacae NICPBP45301, Salmonella typhi NICPBP50097,
Acinetobacter anitratus NICPBP25001, Proteus
morganli NICPBP49086, Proteus
rettgeri NICPBP49006, Shigella
dysenteriae, and Shigella flexneri). This lack of efficacy may be attributed to their
poor ability to penetrate the additional outer membrane
barrier of Gram-negative bacteria[36].
In addition to the Gram-positive and -negative bacteria
tested, these compounds also exhibited bactericidal
properties against Bacillus cereus (MIC=4_32 µg/mL),
Bacillus subtilis (MIC=2_16 µg/mL),
Mycobacterium phlei (MIC=4_32 µg/mL), and
Candida albicans (MIC =8_32 µg/mL).
Interestingly, the 2 series of compounds were highly
efficacious in suppressing the growth of drug-resistant strains
of Gram-positive bacteria, including MRSA, VRE,
vancomycin-intermediate Staphylococci (VISA), and
methicillin-resistant coagulase-negative
Staphylococci (MRCNS; Table 3). The effects on the 4 strains of drug-resistant bacteria
were similar to that observed with drug-susceptible strains
of bacteria such as Staphylococcus
aureus ATCC 29213, Staphylococcus
aureus ATCC 25923, and Staphylococcus
epidermidis ATCC12228 (Table 2).
The above results (Tables 1,2) allowed us to draw some
conclusions. The introduction of halogen atoms resulted in
a reasonable inhibitory activities, whereas compounds
lacking substitutes (A1 and B1) are less active. We also
attempted to increase the aqueous solubility of the compounds
by introducing amino and hydroxyl groups on the phenyl
group, as shown with compounds A5_6 and B5_6, but we
observed a drastic decrease in their antibacterial effects.
However, substitution by the hydrophobic groups seemed
to improve the in vitro MIC values. The benzyloxy group
(B8) brought about moderate activity.
Further introduction of a benzoyl group to the phenyl
group, giving benzophenone derivatives, elicited better
in vitro MIC values for compounds A8_10
and B10_12. Substitution by the naphthyl group also improved activity
(A20_21 and B18). The modification of the phenyl ring to a
diphenyl ring (A11_15 and B13_17) demonstrated the most potent
antibacterial activity against drug-resistant Gram-positive
bacteria with MIC values of 0.5_8 µg/mL. This may be
attributed to the hydrophobic nature of the diphenyl ring
compared to the benzophenone derivatives. This also indicates
that it is favorable to have the hydrophobic group at the
phenyl site, and bulky hydrophobic groups increase the
activity. Compounds A11 and B13, which were substituted
by a phenyl group, displayed more than a 32-fold increase in
bioactivity in comparison with A1 and B1. A12_14 and
B14-16 with 4-halophenyl substitutions demonstrated a 4- to
16-fold increase in antibacterial effects as opposed to
halogen-substituted phenyl-4-guanidinomethylbenzoate derivatives.
Series A compounds possessed much better bactericidal
efficacy and selectivity against Gram-positive strains than their
counterparts in series B substituted with the same group.
We also synthesized 2 guanidinophenyl derivatives
(E1-2; Table 2), but their activities were reduced compared to A11,
indicating that the methylene group was required in the
series A core structure.
Inhibitory activity against OpdA and OpdB
We next evaluated the inhibitory effects of designed compounds on
2 trypsin-like proteinases, oligopeptidase A (OpdA) and
OpdB isolated from Escherichia
coli[35]. Table 4 summarizes the inhibitory percentage and the 50% inhibition
concentration (IC50) values against OpdA and OpdB of a majority of
the synthesized compounds with MIC values (against
Staphylococcus aureus ATCC25923) lower than 256 µg/mL. It
is remarkable that many compounds showed high inhibitory
effects (low IC50 values) against OpdB. We further studied
the correlation between the MIC values and the inhibitory
effects on OpdB of the series A and B compounds with
basically similar substitutions. A general correlation could be
established between the antibacterial activities
(MIC50 values of the compounds
against Staphylococcus aureus ATCC25923) and inhibitory effects on OpdB
(IC50; Figures 4,5). However, we found that the benzophenone
derivatives (A8_10) did not display this tendency (Figure 4) while
possessing fairly low IC50 values (Table 4). The reason of this
apparent discrepancy between bactericidal activity and the
inhibition on OpdB remains to be investigated. However,
there was a good correlation between the MIC and
IC50 values for all the Series B compounds studied (Figure 5). No
similar trend was found with OpdA.
Discussion
The growing incidence and frequency of bacterial
resistance to current therapeutic agents remains a huge
challenge for infectious disease specialists and pharmaceutical
companies. In order to keep ahead of this growing issue,
novel compounds working by new mechanisms of action are
required. Topping the list of infections of most concern are
MRSA and VRE. As an example, using the baseline data
from 1997, it is shown that in 2002 Staphylococcus aureus
was the most frequently diagnosed pathogen and exhibited
significantly less susceptibility to a variety of antibacterial
agents, clearly indicating the need for continued efforts to
expand the arsenal of drugs
available[37].
It was reported previously that
4-guanidinomethylbenzoic acid arylamides had potent inhibitory effects on gastric
lesions[38]. However, their bactericidal effects were not
examined. In this study, we describe a novel class of
synthetic antimicrobial agents based on a similar structural core
(aryl-4-guanidinomethylbenzoate and
N-aryl-4-guanidinomethylbenzamide derivatives) with a narrow spectrum against
Gram-positive bacteria, including several drug-resistant
strains of clinical importance.
A preliminary structure-activity relationship (SAR)
analysis was performed to identify the active groups on both
series A and B compounds. Substitution by the hydrophobic
groups on the phenyl ring increases the antibacterial activity,
and bulky hydrophobic groups further contribute to this
effect. Series A compounds possessed much better
bactericidal efficacy and selectivity against Gram-positive strains
than their counterparts in series B.
Linezolid, vancomycin, ciprofloxacin, levofloxacin,
gemifloxacin, quinupristin-dalfopristin, and teicoplanin are
common antimicrobial agents used in clinics. Linezolid
resistance (MIC=16_32 µg/mL) was reported recently in clonally
vancomycin-susceptible and -resistant Enterococcus
faecium isolated from a patient after only 12 days of
therapy[39], which indicates the urgency of finding alternative solutions. Table
3 compares the activities of 14 compounds (8 from series A
and 6 from series B) described in this study with a number of
antibiotic agents reported in the literature[40_44]
. The antibacterial activities of A11_15 and A21 are superior to that of
ciprofloxacin against MRSA and VRE. All series A and B
compounds listed display comparable or better efficacy than
ciprofloxacin and levo-floxacin against MRSA, VRE, and
MRCNS, and they are sensitive and effective on VISA. With
reference to the 4 drug-resistant strains, gemifloxacin shows
relatively higher potency than most series A and B
compounds. A11_15 and A21 (i) have comparable efficacies as eperezolid,
but are slightly less active than quinupristin-dalfopristin; (ii)
exhibit an equal potency as linezolid on MRSA, VRE, and
VISA; (iii) show similar MIC values as vancomycin and
teicoplanin against MRSA, and are more effective than
vancomycin and teicoplanin on VRE; and (iv) demonstrate lower
potency to MRCNS than most of the antibiotics compared.
However, B13_18 are in general less efficacious than
A11_15 and A21 (MIC=4_16 µg/mL).
The core structure of both series A and B compounds were
designed based on NE-2001, whose putative target may
involve a proteinase of microbial
origin[22]. OpdA (EC 3.4.24.70) is the major soluble enzyme in
Escherichia coli capable of hydrolyzing the free lipoprotein signal
peptide in vitro[45]. As a member of the Zn metalloprotease
subfamily[46], it is required for the normal development of phage
P22[47] and can degrade the cleaved
lpp signal peptide in
vitro[48]. OpdB (EC 3.4.21.83) is a member of the prolyl oligopeptidase family
of serine peptidases belonging to clan SC, family S9. It is a
trypsin-like proteinase commonly found in ancient
eukaryotic unicellular organisms, Gram-negative bacteria, and
spirochetes[49]. Similar enzymes also exist in some plants and
higher organisms[50,51] and have been implicated in the
pathogenicity of certain bacteria since the enzyme is involved in host
cell invasion by acting as an important virulence
factor[49,52]. OpdB from Trypanosoma
brucei has been identified as a target of several drugs used to treat African trypanosomiasis.
The role of OpdB in the pathogenesis of several parasitic
diseases and the possibility that OpdB represents a novel
target for antimicrobial chemotherapy prompted an analysis
of OpdB homologues from bacterial
pathogens[53]. Although OpdB was not found in Gram-positive bacteria, the
possibility exists that a surrogate molecule may exert similar functions.
It is known that OpdB generates a calcium-signaling factor
that interacts with a receptor on the mammalian cell surface,
mobilizing Ca2+ from intracellular pools and promoting
invasion by Trypanosoma cruzi. The targeted deletion of OpdB
in Trypanosoma cruzi causes significant impairment of their
ability to infect mammalian
cells[54,55]. Therefore, this enzyme has the potential of becoming a therapeutic target.
Indeed, the trypanocidal action of several drugs is highly
correlated with their inhibitory effects on OpdB of a suramin
analogue[56].
The results presented in Table 4 demonstrate that,
similar to 4-tert-butylphenyl ester of GMCHA
(GMCHA-OPhtBu; Figure
6)[35], a synthetic trypsin inhibitor, both
series A and B compounds were capable of inhibiting
enzymatic activities of OpdA and OpdB to various extents, but
they were in general more selective towards OpdB. When
comparing the antibacterial effects (MIC values) of both
series A and B compounds with their ability to inhibit OpdB,
a clear correlation could be established (Figures 4, 5). This
trend was particularly evident with series A and B
compounds substituted by small groups, such as halo- (A2_4
and B2_4), hydroxyl- (A5), t-butyl- (B9) and halophenyl-
(A12_A15 and B14_17) groups. When substitutions were
made with larger or complex groups, such as
4-haloben-zoyloxy (A16 and A17), 4-chlorophenyloxycarbonyl (A18),
and 4-(4-fluorophenyl)benzoyloxy (A19), the correlation
between MIC and OpdB inhibition was diminished. The
analysis leads to our speculation that derivatives of
aryl-4-guanidinomethylbenzoate and
N-aryl-4-guanidino-methylbenzamide may target a putative OpdB-like molecule
in Gram-positive germs to exert antibacterial actions,
although an alternative possibility, that is, the compounds are
acting as detergents and their activities are due to lysis of
the cell membrane of the Gram-positive bacteria, cannot be
ruled out at present.
In summary, we have designed, synthesized, and
evaluated the antibacterial activities of
aryl-4-guanidinomethyl-benzoate and N-aryl-4-guanidinomethylbenzamide
derivatives. Of the compounds tested, A11_15, A20, and A21 displayed
consistent and superior antibacterial effects against a spectrum
of Gram-positive microorganisms, but showed little or no
inhibitory activity against Gram-negative bacteria. Most of
these compounds had comparable in vitro bactericidal
activities against VRE and VISA as linezolid: their growth
inhibitory effects on MRSA were similar to vancomycin, but
were less potent than linezolid and vancomycin against
MRCNS. The N-aryl-4'-guanidinomethylbenzamide
derivatives B13_17 exhibited similar properties, but were less
selective and efficacious. A preliminary SAR analysis was
performed to identify the active groups on these compounds,
and the mechanism of actions may involve the inhibition of
a putative OpdB-like molecule in Gram-positive bacteria.
Acknowledgements
We are indebted to Ms Jie-ying ZHANG for technical
assistance and to Dr Dale E MAIS for critical review of this
manuscript.
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