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Chemical Science
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ARTICLE
Journal Name
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Conclusions
Dis., 2015, 1, 512-522.
DOI: 10.1039/C9SC01405E
S. Wagner, R. Sommer, S. Hinsberger, C. Lu, R. W. Hartmann,
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In summary, we have accomplished the first de novo total
synthesis of pseudopaline (2), a metallophore produced by P.
aeruginosa, in 8 steps from the known L-homoserine 10. The
key synthetic strategy relies on the asymmetric Tsuji-Trost
reaction and Mitsunobu reaction to form the challenging C−N
bonds. The total synthesis along with the natural product
isolation allowed data comparison, which led to the
unambiguous structural assignment of pseudopaline. The
synthetic pseudopaline (2) has shown to transport metals such
as zinc, cobalt, iron, and nickel, but not copper, manganese,
calcium or magnesium. The total synthesis also enabled the
preparation of the inactive epi-pseudopaline (3), which
demonstrated the importance of the (S)-configuration for
metallophore function. The preliminary structure-activity
relationship study indicated that pseudopaline derivative 15c
shows comparable activity to pseudopaline. Moreover, the
pseudopaline-fluorescein conjugate P-FL 16 was prepared and
evaluated. Results showed that P-FL 16 could be transported in
P. aeruginosa. Our study demonstrates the proof-of-concept
that pseudopaline could be used to develop a new “Trojan
horse” antibiotic conjugate. Collectively, this work provides a
solid foundation for further chemical and biological
investigations to uncover the new mechanisms about how this
novel metallophore transports metal ions for bacteria as well as
a guide to develop new effective antibiotics against Gram-
negative bacteria infections.
For reviews on application of siderophores, see: (a) T. A.
Wencewicz and M. J. Miller, Top. Med. Chem., 2017, 26,
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10 M. C. Mastropasqua, M. D'Orazio, M. Cerasi, F. Pacello, A.
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11 J. S. McFarlane, C. L. Davis and A. L. Lamb, J. Biol. Chem., 2018,
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Conflicts of interest
There are no conflicts to declare.
12 V. G. Pederick, B. A. Eijkelkamp, S. L. Begg, M. P. Ween, L. J.
McAllister, J. C. Paton and C. A. McDevitt, Sci. Rep., 2015, 5,
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Acknowledgements
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We thank Dr. Hiu Chun Lam (Peking University) and Dr. Maarten
Vercruysse (Roche) for helpful discussions as well as Prof.
Changwen Jin and Prof. Hongwei Li (Peking University) for the
assistance with NMR analysis. We also thank Prof. Xiaoran He
and Prof. Jiang Zhou for HRMS-MS analysis. Dr. Rongwen Yang
is supported in part by the Postdoctoral Fellowship of Peking-
Tsinghua Center for Life Sciences. Financial support from the
NNSFC (21625201, 21661140001, 91853202 and 21521003),
National Key Research and Development Program of China
(2017YFA0505200) as well as a special research grant from
Roche Pharma Research & Early Development is gratefully
acknowledged.
Notes and references
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2
E. D. Brown and G. D. Wright, Nature, 2016, 529, 336−343.
World Health Organization. WHO publishes list of bacteria for
which
new
antibiotics
are
urgently
needed.
J. De Smet, H. Hendrix, B. G. Blasdel, K. Danis-Wlodarczyk and
R. Lavigne, Nat. Rev. Microbiol., 2017, 15, 517-530.
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