Improved synthesis of biotinol-5′-AMP: Implications for antibacterial discovery

Article abstract of DOI:10.1021/ml500475n

An improved synthesis of biotinol-5′-AMP, an acyl-AMP mimic of the natural reaction intermediate of biotin protein ligase (BPL), is reported. This compound was shown to be a pan inhibitor of BPLs from a series of clinically important bacteria, particularl

Full text of DOI:10.1021/ml500475n

Letter
pubs.acs.org/acsmedchemlett
Improved Synthesis of Biotinol-5′-AMP: Implications for Antibacterial
Discovery
William Tieu,†,⊥,# Steven W. Polyak,*,‡,⊥ Ashleigh S. Paparella,‡ Min Y. Yap,§,∇
Tatiana P. Soares da Costa,‡,○ Belinda Ng,‡ Geqing Wang,‡,◆ Richard Lumb,∥ Jan M. Bell,∥
John D. Turnidge,‡,∥ Matthew C. J. Wilce,§ Grant W. Booker,‡,⊥ and Andrew D. Abell*,†,⊥
†School of Chemistry and Physics, University of Adelaide, Adelaide, South Australia 5005, Australia
‡School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia 5005, Australia
§School of Biomedical Science, Monash University, Victoria 3800, Australia
∥Microbiology and Infectious Diseases Directorate, SA Pathology, Women’s and Children’s Hospital, Adelaide, South Australia 5006,
Australia
⊥Centre for Molecular Pathology, The University of Adelaide, Adelaide, South Australia 5005, Australia
S
* Supporting Information
ABSTRACT: An improved synthesis of biotinol-5′-AMP, an acyl-AMP
mimic of the natural reaction intermediate of biotin protein ligase
(BPL), is reported. This compound was shown to be a pan inhibitor of
BPLs from a series of clinically important bacteria, particularly
Staphylococcus aureus and Mycobacterium tuberculosis, and kinetic
analysis revealed it to be competitive against the substrate biotin.
Biotinol-5′-AMP also exhibits antibacterial activity against a panel of
clinical isolates of S. aureus and M. tuberculosis with MIC values of 1−8
and 0.5−2.5 μg/mL, respectively, while being devoid of cytotoxicity to
human HepG2 cells.
KEYWORDS: Antibiotics, enzyme inhibitors, biotin protein ligase, chemical synthesis, drug design
denylate-forming enzymes play a central role in many key
metabolic pathways such as ribosomal and nonribosomal
biotinol-5′-AMP 2 as a BPL inhibitor, we now report an
expedient method for its synthesis and an investigation of its
activity profile against clinically significant bacteria.
A
peptide synthesis, fatty acid synthesis, and enzyme regulation.
As such they are of significant interest as potential drug
targets.1,2 These enzymes function by activating a carboxylate
metabolite on reaction with ATP to form an acyl-AMP
intermediate, which then reacts with a nucleophile to generate
the desired product (Figure 1). The acyl-AMP reaction
intermediates possess a high binding affinity for the enzyme,
often 2−3 orders of magnitude greater than the carboxylic acid
or ATP substrates.3,4
The inhibition of biotinyl-5′-AMP 1, one such intermediate
produced by the biotin protein ligase (BPL) catalyzed reaction
of biotin and ATP, has attracted recent interest as a potential
new class of antibiotic.5,6 An important approach to these
inhibitors involves replacing the hydrolytically unstable acyl
phosphate linker of 1 with a more stable bioisostere, as in
biotinol-5′-AMP 2.6,7 This phosphodiester mimic is a potent
inhibitor of BPLs from S. aureus, Escherichia coli, and Homo
sapiens.6,8 However, its antibacterial properties have not been
investigated. Other acyl phosphate bioisosteres used in this
context include, sulfonyl and 1,2,3-triazole groups, among
others.5,6,9−25 Importantly, acyl-AMP mimics (containing
sulfonmyl and 1,2,3-triazole isosteres, see 3 and 4 in Figure
1) have been shown to be potent agents against M. tuberculosis
and S. aureus, respectively.26 Given the central importance of
Biotinol-5′-AMP 2 is reportedly prepared according to a
modified “phosphodiester” procedure as shown in Scheme 1.7
However, in our hands this procedure gave an unsatisfactory
overall yield of 9% from adenosine 5. The key limitation with
this procedure was a DCC mediated coupling of 6 and 8 to give
phosphodiester 9, with subsequent in situ deprotection of the
acetonide group to give 2. An overall yield of 15% was obtained
over these two steps. Attempts to optimize the DCC coupling
step using other solvents, particularly pyridine or DMF, or
longer reaction times (up to 48 h) failed to improve the yield.
The use of other acids for the deprotection (20−60% acetic
acid instead of TFA) similarly failed to improve the efficiency of
this sequence. Thus, an alternative approach to biotinol-5′-
AMP 2 was investigated that would avoid the problematic DCC
coupling and hemiacetal deprotection steps, see Scheme 2. This
methodology was then used to prepare sufficient quantities of 2
for antimicrobial studies. A very recent report, investigating
biotinol-5′-AMP 2 and its phosphite analogues as human BPL
Received: November 20, 2014
Accepted: December 11, 2014
Published: December 11, 2014
© 2014 American Chemical Society
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ACS Medicinal Chemistry Letters
Letter
a
Scheme 2
a
Reagents and conditions: (a) ClP(OMe)N(iPr)2, Et3N, DCM; (b)
(i) SOCl2, MeOH; (ii) DMTrCl, DCM; (iii) LiAlH4, THF; (c) (i) 5-
ETT, MeCN; (ii) tBuOOH; (d) (i) 10% TFA, DCM; (ii) NH3OH,
MeOH/H2O; (iii) NaI, H2O.
Figure 1. General catalytic mechanism of adenylate forming enzymes
(top). Chemical structures are shown for the acyl-AMP intermediate
of BPL biotinyl-5′-AMP (1) and its phosphodiester mimic biotinol-5′-
AMP (2), acyl-sulfamide biotin adenosine monosulfamide (Bio-AMS)
(3), and 1,2,3-triazole (4).
biotinol 12. The phosphoramidate 11 was then coupled to
biotinol 12 using 5-(ethylthio)-1H-tetrazole, with oxidation of
the resulting phosphite with tert-butyl hydrogen peroxide
(TBHP) and immediate quenching with sodium metabisulfite
to give phosphotriester 13a in 59%. Attempts at coupling 11
with 12 without the addition of bisulfate gave predominately
the overoxidized sulfone analogue 13b, as confirmed by mass
spectrometry, see Supporting Information. The formation of
13b was judged to be irreversible, as reduction of 13b to 13a
would have resulted in epimerization of the biotin alkyl chain.29
A sequential treatment of phosphotriester 13a with TFA,
NH3OH, and NaI followed by purification of the crude product
by reverse phase HPLC gave 2 in >95% purity. This sequence
gave biotinol-5′-AMP 2 with an overall 2-fold improvement in
yield starting from adenosine 10 compared to the earlier
phosphodiester synthesis.
a
Scheme 1
The inhibitory activity of the newly synthesized biotinol-5′-
AMP 2 was investigated against a panel of BPLs using an in
vitro biotinylation assay that measures the incorporation of
radiolabeled biotin onto an acceptor protein.6,30 The activity of
each enzyme was determined in the presence of varying
concentrations of biotinol-5′-AMP 2. The apparent inhibition
constants (Kiapp) were calculated using the Morrison equation
for tight binding inhibitors as most of the Kiapp values were
within 10-fold of the concentration of BPL employed in the
assay. Biotinol-5′-AMP 2 inhibited all five clinically relevant
microbial BPLs with the greatest potency against S. aureus
(Kiapp = 18 nM) and M. tuberculosis (Kiapp = 52 nM). It also
inhibited human BPL with a Kiapp of 182 nM. Thus, biotinol-5′-
AMP 2 is a pan BPL inhibitor, presumably since its structure
closely resembles that of the natural reaction intermediate
biotinyl-5′-AMP 1, which is common to all BPLs.
a
Reagents and conditions: (a) (i) POCl3, PO(Et)3; (ii) TEAB buffer;
(b) (i) SOCl2, MeOH; (ii) LiAlH4, THF; (c) DCC, py; (d) 60%
AcOH(aq)
.
inhibitors, implemented a similar strategy to Scheme 2 for the
synthesis of biotinol-5′-AMP 2.25
The alternative “phosphoramidate” synthesis commenced
with the conversion of N-benzoyl protected adenosine 10 to
the corresponding phosphoramidate 11 in 67% yield.27 Biotinol
12 was synthesized as previously reported.28 Specifically, biotin
7 was esterified under acidic conditions to the corresponding
methyl ester, followed by selective N-tritylation of the ureido
ring of biotin methyl ester and a subsequent reduction to give
It has previously been established that biotin and ATP bind
to BPL in an ordered manner, with biotin binding first.6,31 This
suggests that biotinol-5′-AMP 2 would be a competitive
inhibitor against biotin. In support, our published X-ray crystal
structures of S. aureus BPL in complex with biotin [PDB
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ACS Medicinal Chemistry Letters
Letter
3RKY]32 and biotinol-5′-AMP 2 [PDB 4DQ2]6 demonstrate
that both compounds occupy the same binding pocket. The
activity of S. aureus BPL was measured in the presence of
varying concentrations of both inhibitor and biotin in order to
define the kinetics of inhibition.33 Lineweaver−Burk double-
reciprocal plots of 1/enzyme velocity versus 1/biotin
concentration gave four straight lines that had a common y-
intercept (Figure 2). The data demonstrated that increasing
Table 2. In Vitro Susceptibility Assay of Biotinol-5′-AMP 2
against a Series of Bacterial Strains
MIC
bacterium class
M. tuberculosis
strains
H37Rv
resistance
(μg/mL)
2.5
M. tuberculosis
M. tuberculosis
M. tuberculosis
M. tuberculosis
M. tuberculosis
S. aureus (n = 8)
S. aureus (n = 8)
#37892293
#3688023
BCG (SI)
Who-185
Who-1841
MSSA
2.5
0.5
pyrazinamide
rifampicin
isoniazid
resistant
2.5
0.5
2−4
2−8
1−4
MRSA
methicillin
Coagulase negative staphylococci
(n = 7)
Escherichia coli
ATCC
25922
>128
Enterococcus faecalis (n = 3)
Enterococcus faecium (n = 5)
>128
>128
>200
Homo sapiens, HepG2 cell line HB8065
uptake between the different species. Likewise, M. tuberculosis
was sensitive to biotinol-5′-AMP 2, including strains resistant to
front line antibiotics. In particular, biotinol-5′-AMP inhibited
growth of WHO-1841 at 0.5 μg/mL, a strain resistant to the
fatty acid biosynthesis inhibitor isoniazid. The notable
exception was the pyrazinamide resistant strain BCG (SI)
that was also insensitive to biotinol-5′-AMP 2 for reasons that
are not clear. It is noteworthy that, although biotinol-5′-AMP 2
inhibited human BPL in vitro, the compound showed no cell
cytotoxicity (CC50) against the human liver cell line HepG2 at
concentrations as high as 200 μg/mL, providing a therapeutic
index (CC50/MIC) of >25−400-fold, based upon the MICs for
S. aureus and M. tuberculosis, respectively. The observed MIC
values of biotinol-5′-AMP 2 against M. tuberculosis (0.5−2.5
μg/mL) are comparable with acyl-AMP mimic bio-AMS 3
(0.1−0.5 μg/mL).5 Interestingly, while both 2 and 3 are active
against M. tuberculosis, only 2 is cytotoxic over Gram-positive S.
aureus.
In summary, an improved synthesis of biotinol-5′-AMP 2 and
its subsequent biological characterization are reported. The new
approach gives an improved yield of 29%. Enzyme inhibition
and in vitro antibacterial susceptibility assays revealed that
biotinol-5′-AMP 2 is a prime candidate for further development
as a new class of antimicrobial agent. While this compound is a
pan BPL inhibitor, it possesses selective antimicrobial inhibitory
activity toward Gram-positive microbes over Gram-negative
and importantly human cell lines. Significantly, MIC values
between 0.5−2.5 μg/mL were obtained against resistant strains
of M. tuberculosis.
Figure 2. Kinetic analysis of inhibitor binding. S. aureus BPL activity
was measured in the presence of inhibitor and varying concentrations
of biotin. Lineweaver−Burk curves are shown for 3H-biotin. The insert
is an expanded view close to the origin showing the curves intersecting
the y-axis. The concentrations of 2 employed in the assays were 0
(blue curves), 20 nM (orange curves), 100 nM (black curves), and 200
nM (red curves). Data points are the mean SEM for three replicates.
concentrations of inhibitor were accompanied by increases in
the KM for biotin, while the Vmax remained unchanged. This
supports the proposal that biotinol-5′-AMP 2 is a competitive
inhibitor of biotin. Accordingly, the Kiapp were extrapolated for
each species of BPL using the apparent KM values for biotin
(Table 1).34
Table 1. In Vitro Biotinylation Assay Results for Biotin and
Inhibition Constants for Biotinol-5′-AMP 2
app
KM biotin
(μM)
Ki
biotinol-5′-AMP 2
biotin protein ligase
(nM)
Escherichia coli
0.3
1.0
2.0
0.3
0.5
1.1
87
Staphylococcus aureus
Klebsiella pneumoniae
Acinetobacter calcoaceticus
Mycobacterium tuberculosis
Homo sapiens
18
482
461
52
ASSOCIATED CONTENT
■
182
S
* Supporting Information
Biological assays, synthetic procedures, and data for selected
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Finally, the antimicrobial activity of biotinol-5′-AMP 2 was
assessed against a library of clinically important bacteria using a
microdilution broth assay. The resulting minimal inhibitory
concentrations (MIC) are shown in Table 2. Encouragingly,
biotinol-5′-AMP 2 was effective against staphylococci with
minimal inhibitory concentrations varying from 1−8 μg/mL,
but not enterococci nor E. coli. The difference in antibacterial
activity observed here may be due to differences in compound
AUTHOR INFORMATION
■
Corresponding Authors
*Tel: +61 8 8313 6042. E-mail: steven.polyak@adelaide.edu.au.
*Tel: +61 8 8313 5652. E-mail: andrew.abell@adelaide.edu.au.
218
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ACS Medicinal Chemistry Letters
Letter
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Present Addresses
#School of Medical Sciences (Pharmacology) and Bosch
Institute, The University of Sydney, Sydney, New South
Wales 2006, Australia.
∇CSL Limited, 45 Poplar Road, Parkville, Victoria 3052,
Australia.
○School of Biomedical Science, Charles Sturt University,
Wagga Wagga, New South Wales 2650, Australia.
◆Medicinal Chemistry, Monash Institute of Pharmaceutical
Sciences, Monash University, Parkville, Victoria 3052, Australia.
Author Contributions
The manuscript was written through contributions of all
authors. Medicinal chemistry was performed by W.T. and
A.D.A., biochemical assays were performed by A.S.P., B.N.,
M.Y.Y., T.P.S., and G.W. under the guidance of S.W.P.,
M.C.J.W., and G.W.B., antibacterial susceptibility assays were
performed by R.L., J.M.B., and J.D.T., and cell culture assays
were performed by S.W.P.
Funding
This work was supported by the National Health and Medical
Research Council of Australia (applications APP1011806 and
APP1068885), the Centre for Molecular Pathology, University
of Adelaide, and Adelaide Research and Innovation’s
Commercial Accelerator Scheme. We are grateful to the
Carthew family for their financial support of this work.
M.C.J.W. is an Australian National Health and Medical
Research Council of Australia Senior Research Fellow.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We are grateful to the Australian National Fabrication Facility
for providing access to analytical HPLC. We also thank Dr. Ivan
Bastian for his critical comments on the manuscript.
ABBREVIATIONS
■
BPL, biotin protein ligase; MIC, minimal inhibitory concen-
tration
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