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ChemComm
DOI: 10.1039/C7CC07285F
COMMUNICATION
Journal Name
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S. Yoganathan and S. J. Miller, J. Med. Chem., 2015, 58, 2367.
K. L. Brown and R. E. W. Hancock, Curr. Opin. Immunol., 2006, 18, 24.
0. R. E. Hancock and H. G. Sahl, Nat. Biotechnol., 2006, 24, 1551.
1. D. K. Mercer and D. A. O'Neil, Future Med. Chem., 2013, 5, 315.
2. R. E. W. Hancock, K. L. Brown and N. Mookherjee, Immunobiology, 2006,
211, 315.
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3. K. Matsuzaki, Biochimi. Biophys. ACTA Biomembr., 2009, 1788, 1687.
4. D. Sengupta, H. Leontiadou, A. E. Mark and S. J. Marrink, Biochim.
Biophys. Acta., 2008, 1778, 2308.
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1
1
1
1
5. G. N. Tew, R. W. Scott, M. L. Klein and W. F. DeGrado, Acc. Chem. Res.,
2010, 43, 30.
6. P. Teng, D. Huo, A. Nimmagadda, J. Wu, F. She, M. Su, X. Lin, J. Yan, A.
Cao, C. Xi, Y. Hu and J. Cai, J. Med. Chem., 2016, 59, 7877.
7. S. Choi, A. Isaacs, D. Clements, D. Liu, H. Kim, R. W. Scott, J. D. Winkler
and W. F. DeGrado, Proc. Natl. Acad. Sci. U.S.A., 2009, 106, 6968.
8. Y. Niu, S. Padhee, H. Wu, G. Bai, Q. Qiao, Y. Hu, L. Harrington, W. N. Burda,
L. N. Shaw, C. Cao and J. Cai, J. Med. Chem., 2012, 55, 4003.
Fig. 4 In vivo efficacy of the compounds 7 and 8 in thigh‐infection mouse model.
Neutropenic mice (n = 4 per group) were inoculated in the posterior thigh muscles with
S. aureus ATCC 33591 at 1 × 10 CFU per thigh and then treated with 7 and 8 (5 mg/kg
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per dose) by i.v. bolus injection in the tail vein at 1 and 7 h after infection.
9. Y. Li, H. Wu, P. Teng, G. Bai, X. Lin, X. Zuo, C. Cao and J. Cai, J. Med. Chem.,
remarkable potency against a panel of multidrug‐resistant
2015, 58, 4802.
Gram‐positive and Gram‐negative bacteria. Although other 20. C. Ghosh, G. B. Manjunath, P. Akkapeddi, V. Yarlagadda, J. Hoque, D. S.
Uppu, M. M. Konai and J. Haldar, J. Med. Chem., 2014, 57, 1428.
1. B. Mensa, Y. H. Kim, S. Choi, R. Scott, G. A. Caputo and W. F. DeGrado,
Antimicrob. Agents Chemother., 2011, 55, 5043.
2. B. Wang, B. Pachaiyappan, J. D. Gruber, M. G. Schmidt, Y. M. Zhang and
P. M. Woster, J. Med. Chem., 2016, 59, 3140.
antimicrobial mechanisms cannot be excluded, our studies
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suggest that these compounds could kill bacteria rapidly by
disrupting bacterial membranes, a mechanism analogous to
that of HDPs. This is consistent to their amphipathic structures,
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with the one having proper balance of hydrophobicity and 23. C. M. Raulji, K. Clay, C. Velasco and L. C. Yu, J. Pediatr. Hematol. Oncol.,
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015, 32, 315.
cationic charge showing the most potent antibacterial activity.
The hypothesis is further supported by the fact that the
susceptibility of MRSA bacteria to the lead compounds
remained nearly unchanged even after 14 passages.
Furthermore, antibiotic therapeutic potential of these
molecules was confirmed in the MRSA‐infected thigh burden
mouse model. Our work illustrated the potential of bis‐cyclic
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4. M. Grare, H. M. Dibama, S. Lafosse, A. Ribon, M. Mourer, J. B. Regnouf‐
de‐Vains, C. Finance and R. E. Duval, Clin. Microbiol. Infect., 2010, 16, 432.
5. R. Fleeman, T. M. LaVoi, R. G. Santos, A. Morales, A. Nefzi, G. S. Welmaker,
J. L. Medina‐Franco, M. A. Giulianotti, R. A. Houghten and L. N. Shaw, J.
Med. Chem., 2015, 58, 3340.
6. S. Lin, J. J. Koh, T. T. Aung, F. Lim, J. Li, H. Zou, L. Wang, R.
Lakshminarayanan, C. Verma, Y. Wang, D. T. Tan, D. Cao, R. W. Beuerman,
L. Ren and S. Liu, J. Med. Chem., 2017, 60, 1362.
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guanidines for the development of potent antimicrobial 27. J. J. Koh, S. Lin, T. T. Aung, F. Lim, H. Zou, Y. Bai, J. Li, H. Lin, L. M. Pang, W.
L. Koh, S. M. Salleh, R. Lakshminarayanan, L. Zhou, S. Qiu, K. Pervushin, C.
Verma, D. T. Tan, D. Cao, S. Liu and R. W. Beuerman, J. Med. Chem., 2015,
molecules with molecular masses in the range of 600‒900.
Further studies on optimization of activity and selectivity, as
well pharmacokinetic assessments are underway in our lab.
This work was supported by NSF CAREER 1351265 and NIH
58, 739.
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8. R. P. Kowalski, E. G. Romanowski, K. A. Yates and F. S. Mah, J. Ocul.
Pharmacol. Ther., 2016, 32, 23.
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R01GM112652‐01A1. This work has been supported in part by 29. F. Weis, A. Beiras‐Fernandez and G. Schelling, Curr. Opin. Investig. Drugs,
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008, 9, 879.
0. D. Yahav, L. Farbman, L. Leibovici and M. Paul, Clin. Microbiol. Infect.,
012, 18, 18.
the Mass Spectrometry and Peptide Facility, Department of
Chemistry, University of South Florida.
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31. D. Davies, Nat. Rev. Drug. Discov., 2003, 2, 114.
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2. H.‐C. Flemming, J. Wingender, U. Szewzyk, P. Steinberg, S. A. Rice and S.
Kjelleberg, Nat. Rev. Microbiol., 2016, 14, 563.
Conflicts of interest
There are no conflicts to declare.
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3. S. Padhee, Y. Li and J. Cai, Bioorg. Med. Chem. Lett., 2015, 25, 2565‐2569.
4. T. Bjarnsholt, O. Ciofu, S. Molin, M. Givskov and N. Hoiby, Nat. Rev. Drug.
Discov., 2013, 12, 791.
35. A. Brauner, O. Fridman, O. Gefen and N. Q. Balaban, Nat. Rev. Microbiol.,
2
016, 14, 320.
Notes and references
3
6. S. R. Park, A. Tripathi, J. Wu, P. J. Schultz, I. Yim, T. J. McQuade, F. Yu, C.‐
J. Arevang, A. Y. Mensah, G. Tamayo‐Castillo, C. Xi and D. H. Sherman,
Nat. Commun., 2016, 7, 10710.
7. S. Fernandez‐Lopez, H.‐S. Kim, E. C. Choi, M. Delgado, J. R. Granja, A.
Khasanov, K. Kraehenbuehl, G. Long, D. A. Weinberger, K. M. Wilcoxen
and M. R. Ghadiri, Nature, 2001, 412, 452.
8. A. Vallon‐Eberhard, A. Makovitzki, A. Beauvais, J.‐P. Latgé, S. Jung and Y.
Shai, Antimicrob. Agents Chemother., 2008, 52, 3118.
9. I. S. Radzishevsky, S. Rotem, D. Bourdetsky, S. Navon‐Venezia, Y. Carmeli
and A. Mor, Nat. Biotechnol., 2007, 25, 657.
0. D. Andes, M. L. van Ogtrop, J. Peng and W. A. Craig, Antimicrob. Agents
1
2
.
.
S. B. Levy and B. Marshall, Nat. Med., 2004, 122.
M. P. Doyle, G. H. Loneragan, H. M. Scott and R. S. Singer, Compr. Rev.
Food Sci. Food Saf., 2013, 12, 234.
3
3
4
.
.
Y. Niu, R. E. Wang, H. Wu and J. Cai, Future Med. Chem., 2012, 4, 1853.
A. K. Marr, W. J. Gooderham and R. E. Hancock, Curr. Opin. Pharmacol.,
2006, 6, 468.
3
3
4
5
6
.
.
WHO, Antimicrobial resistance: global report on surveillance. 2014.
P. I. O'Daniel, Z. Peng, H. Pi, S. A. Testero, D. Ding, E. Spink, E. Leemans,
M. A. Boudreau, T. Yamaguchi, V. A. Schroeder, W. R. Wolter, L. I. Llarrull,
W. Song, E. Lastochkin, M. Kumarasiri, N. T. Antunes, M. Espahbodi, K.
Lichtenwalter, M. A. Suckow, S. Vakulenko, S. Mobashery and M. Chang,
J. Am. Chem. Soc., 2014, 136, 3664.
Chemother., 2002, 46, 3484.
7.
L. L. Ling, T. Schneider, A. J. Peoples, A. L. Spoering, I. Engels, B. P. Conlon,
A. Mueller, T. F. Schaberle, D. E. Hughes, S. Epstein, M. Jones, L. Lazarides,
V. A. Steadman, D. R. Cohen, C. R. Felix, K. A. Fetterman, W. P. Millett, A.
G. Nitti, A. M. Zullo, C. Chen and K. Lewis, Nature, 2015, 517, 455.
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