Angewandte Chemie International Edition
10.1002/anie.202003094
Table 2. Expanded Profiling of 11 against Mtb.
11
Rifampicin (RIF)
Isoniazid (INH)
Levofloxacin (FQ)
organism
IC50
MIC
IC50 (M)
MIC
IC50
MIC
IC50
MIC
(
M)
(M)
(M)
(M)
(M)
(M)
(M)
Mtb H37Rv
0.16
0.54
6.7
1.4
8.3
50
0.004
0.002
―
0.009
0.03
―
―
―
―
―
Mtb H37Rv (low O
2
)
―
―
―
―
Mtb H37Rv (THP-1 cells)
0.14
0.31
>200
>200
0.15
0.41
0.22
0.33
>200
>200
0.6
―
―
R
Mtb FQ
1.6
15
0.013
0.014
0.0061
0.75
0.017
0.017
0.01
3.7
57
100
5.2
5.4
3.4
5.1
R
Mtb INH
1.2
10
3.2
3.2
2.6
2.8
R
Mtb INH
0.94
1.2
9.2
17
R
Mtb RIF
R
Mtb RIF
0.32
2.8
>50
>50
0.34
Keywords: antibiotic • ribosome • amicetin • blasticdin S •
In conclusion, this study provides the first structural
characterization of an inhibitor of the ribosomal P-site that
selectively inhibits prokaryotic translation. Importantly, it
demonstrates that amicetin shares significant overlap with
the blasticidin S binding site and mimics the -N-methyl -
arginine with the dimethylamino group of the cytosamine
sugar, not the -methylserine substituent as previously
thought. This example provides for a unified picture of
how the aminohexopyranose- and peptidyl-nucleoside
antibiotics inhibit translation. These results further
demonstrate that amicetin can be synthetically minimized,
to provide analogues that are more stable, retain potency
and selectivity for inhibition of prokaryotic protein
translation. Taken together this supports that the
translation inhibitor
[
1]
WHO (2017) Global Tuberculosis Report 2017, p 147, World Health
Organization, Geneva.
[
[
2]
3]
J. Chen, K. Raymond, K. Ann. Clin. Microbiol. Antimicrob. 2006, 5:3.
N. Hariprasad, N.; S. C. Nallani, R. S. Sane, D. J. Buckley, A. R.
Buckley, P. B. J. Desai, P. B. J. Clin. Pharmacol. 2004, 44, 1273-1281.
http://www.tballiance.org/ pipeline/discovering-new-drugs.php
[
[
4]
5]
[6]
J. W. Hinman, E. L. Caron, C. DeBoer J. Am. Chem. Soc. 1953, 75,
5864-5866.
[7]
C. DeBoer, E. L. Caron, J. W. Hinman J. Am. Chem. Soc. 1953, 75,
499-500.
[
[
8]
9]
Amicetin was re-isolated following the scaled down procedure based on
the published report of Hinman and co-workers (ref. 6).
aminohexopyranose nucleoside antibiotics provide
a
(a) Amicetin re-tested for its biological activity against M. tuberculosis
H37Ra and CEM-TART leukemia cell lineage as described: J. C. Noro,
L. R. Barrows, O. G. Gideon, C. M. Ireland, M. Koch, T. Matainaho, P.
Piskaut, C. D. Pond, T. S. Bugni J. Nat. Prod. 2008, 71, 1623-1627. (b)
O. A. Fahmi, M. Kish, S. Boldt, R. S. Obach Drug Metab. Dispos. 2010,
tractable scaffold for the development of new anti-
tubercular agents.
3
8, 16051611.
Acknowledgements
[
[
10] (a) Haskell, T. H. J. Am. Chem. Soc. 1958, 80, 747-751. (b) M. Konishi,
M. Naruishi, T. Tsuno, H. Tsukiura, H. Kawaguchi J. Antibiot. 1973, 26,
Funding for this research was provided by the ACS-Teva
Pharmaceuticals Mark A. Goshko Memorial Grant Program and
the National Institutes of Health (NIAID 1R01AI127724 and
Fogarty International Center Grant ICBG 5U01TW006671). This
work was also supported by National Institutes of Health and the
National Institute of Allergy and Infectious Diseases, Contract
No. HHSN272201100009I. We thank Profs. Alexander Mankin
and Yury Polikanov for helpful discussions and Michael
Landward for help with biochemical assays. NMR results
included in this report were recorded at the David M. Grant NMR
Center, a University of Utah Core Facility. Funds for construction
of the Center and the helium recovery system were obtained
from the University of Utah and the National Institutes of Health
awards 1C06RR017539-01A1 and 3R01GM063540-17W1
respectively. NMR instruments were purchased with support of
the University of Utah and the National Institutes of Health
award 1S10OD25241-01.
757-764. c) J. Itoh, S. Miyadoh J. Antibiot. 1992, 45, 846-853.
11]
(a) Y.-Y. Bu, H. Yamazaki, K. Ukai, M. Namikoshi Mar. Drugs 2014, 12,
6102-6112. (b) K. Haneda, M. Shinose, A. Seino, N. Tabata, H.
Tomoda, Y. Iwai, S. Omura J. Antibiot. 1994, 47, 774-781. (c) J. Fu, S.
Laval, B. Yu J. Org. Chem. 2018, 83, 7076-7084.
[
[
12] (a) S. Takeuchi, K. Hirayama, K. Ueda, H. Sakai, H. Yonehara J. Antibiot.
1
958, 11, 1-5. (b) H. Yamaguchi, C. Yamamoto, N. Tanaka J. Biochem.
965, 57, 667-677.
1
13] J. J. Fox, Y. Kuwada, K. A. Watanabe, T. Ueda, E. B. Whipple
Antimicrob. Agents Chemother. 1964, 518-529.
[14] N. Katayama, S. Fukusumi, Y. Funabashi, T. Iwahi, H. Ono J. Antibiot.
1993, 46, 606-613.
[
15] J. L. Hansen, P. B. Moore, T. A. Steitz J. Mol. Biol. 2003, 330, 1061-
075.
1
[
16] E. Svidritskiy, C. Ling, D. N. Ermolenko, A. A. Korostelev Proc. Nat.
Acad. Sci. USA 2013, 110, 12283-1288.
[
[
17] S. Pestka J. Biol. Chem. 1972, 247, 4669-4678.
18] (a) J. J. Fox, K. A. Watanabe, A. Bloch. Prog. Nucleic Acid Res. 1966, 5,
251-313. (b) F. W. Lichtenhaler, G. Trummlitz FEBS Lett. 1974, 38,
237-242.
[
19] I. Leviev, C. Rodriguez-Fonseca, H. Phan, R. A. Garrett, G. Heilek, H. F.
Noller, A. S. Mankin Eur. Mol. Biol. Org. J. 1994, 13, 1682-1686.
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