Mimicry of Antimicrobial Host-Defense Peptides

 

Top row: When designing a host-defense peptide (HDP) mimic, the most common approach involves designing a globally amphiphilic helix.  We show, with this nylon-3 polymer system (middle left), that a globally amphiphilic, irregular structure can also act as an effective HDP mimic.

Right: Activity as a function of percent cationic subunit (y) in polymers 3y.  For polymer 363, MHC/MIC = 32, demonstrating substantial selectivity for bacteria over eukaryotic cells.

Bottom left: Activity of polymer 360 compared to that of three widely-studied HDP and an artificial mutant known to be more active than natural magainin.1

 

Recent Publications:

13. "A cationic polymer that shows high antifungal activity against diverse human pathogens" Rank, L. A.; Walsh, N. M.; Liu, R.; Lim, F. Y.; Bok, J. W.; Huang, M.; Keller, N. P.; Gellman, S.H.; Hull, C. M. Antimicrob. Agents Chemother. doi:10.1128/AAC.00204-17

12. "Single-cell, Time-resolved Antimicrobial Effects of a Highly Cationic, Random Nylon-3 Copolymer on Live E. coli." Choi, H.; Chakraborty, S.; Liu, R.; Gellman, S.H.; Weisshaar, J.C. ACS Chem. Biol. 2016, 11, 113.

11. “Nylon-3 polymers active against drug-resistant Candida albicans biofilms.” Liu R, Chen X, Falk SP, Masters KS, Weisblum B, Gellman SH. J. Am. Chem. Soc. 2015, 137, 2183.

10. “Synthetic polymers active against Clostridium difficile vegetative cell growth and spore outgrowth." Liu R, Suárez JM, Weisblum B, Gellman SH, McBride SM J. Am. Chem. Soc. 2014, 136, 14498

9. “Ternary nylon-3 copolymers as host-defense peptide mimics: beyond hydrophobic and cationic subunits." Chakraborty S, Liu R, Hayouka Z, Chen X, Ehrhardt J, Lu Q, Burke E, Yang Y, Weisblum B, Wong GC, Masters KS, Gellman SH J. Am. Chem. Soc. 2014, 136, 14530.

8. “Medium effects on minimum inhibitory concentrations of nylon-3 polymers against E. coli." Choi H, Chakraborty S, Liu R, Gellman SH, Weisshaar JC PLoS One 2014, 9, e104500.

7. “Two interdependent mechanisms of antimicrobial activity allow for efficient killing in nylon-3-based polymeric mimics of innate immunity peptides.” Lee M, Chakraborty S, Schmidt NW, Murgai R, Gellman SH, Wong GC. Biochim. Biophys. Acta. 2014, 1838, 2269.

6. "Tuning the Biological Activity Profile of Antibacterial Polymers via Subunit Substitution Pattern." Liu R., Chen X., Chakraborty S., Lemke J.J., Hayouka Z., Chow C., Welch R.A, Weisblum B, Masters KS, Gellman SH., J. Am. Chem. Soc. 2014, 136, 4410.

5. "Nylon-3 polymers with selective antifungal activity.”, Liu R, Chen X, Hayouka Z, Chakraborty S, Falk SP, Weisblum B, Masters KS, Gellman SH. J. Am. Chem. Soc. 2013, 135, 5270. 

4.  “C-terminal functionalization of nylon-3 polymers: effects of C-terminal groups on antibacterial and hemolytic activities.”, Zhang, J.; Markiewicz, M.J.; Mowery, B.P.; Weisblum, B.; Stahl, S.S.; Gellman, S.H., Biomacromolecules. 2012, 13, 323-331.

3.  "Structure-Activity Relationships Among Random Nylon-3 Copolymers that Mimic Antibacterial Host-Defense Peptides," B. M. Mowery, A. M. Lindner,  B. Weisblum, S. S. Stahl and S. H. Gellman J. Am. Chem. Soc. 2009, 131, 9735.

2.  "Dual Mechanism of Bacterial Lethality for a Cationic Sequence-Random Copolymer that Mimics Host-Defense Antimicrobial Peptides," R. F. Epand, B. P. Mowery, S. E. Lee, S. S. Stahl, R. I. Lehrer, S. H. Gellman and R. M. Epand J. Mol. Biol. 2008, 379, 38.

1. "Mimicry of Antimicrobial Host-Defense Peptides by Random Co-Polymers," B. P. Mowery, S. E. Lee, D. A. Kissounko, R. F. Epand, R. M. Epand, B. Weisblum, S. S. Stahl and S. H. Gellman J. Am. Chem. Soc. 2007, 129, 15474.