Self-derived structure-disrupting peptides targeting methionine aminopeptidase in pathogenic bacteria: a new strategy to generate antimicrobial peptides

Jian Zhan, Husen Jia, Evgeny A. Semchenko, Yunqiang Bian, Amy M. Zhou, Zhixiu Li, Yuedong Yang, Jihua Wang, Sohinee Sarkar, Makrina Totsika, Helen Blanchard, Freda E.C. Jen, Qizhuang Ye, Thomas Haselhorst, Michael P. Jennings, Kate L. Seib, Yaoqi Zhou

Research output: Contribution to journalArticle

Abstract

Bacterial infection is one of the leading causes of death in young, elderly, and immune-compromised patients. The rapid spread of multi-drug-resistant (MDR) bacteria is a global health emergency and there is a lack of new drugs to control MDR pathogens. We describe a heretofore-unexplored discovery pathway for novel antibiotics that is based on self-targeting, structure-disrupting peptides. We show that a helical peptide, KFF- EcH3, derived from the Escherichia coli methionine aminopeptidase can disrupt secondary and tertiary structure of this essential enzyme, thereby killing the bacterium (including MDR strains). Significantly, no detectable resistance developed against this peptide. Based on a computational analysis, our study predicted that peptide KFF- EcH3 has the strongest interaction with the structural core of the methionine aminopeptidase. We further used our approach to identify peptide KFF- NgH1 to target the same enzyme from Neisseria gonorrhoeae. This peptide inhibited bacterial growth and was able to treat a gonococcal infection in a human cervical epithelial cell model. These findings present an exciting new paradigm in antibiotic discovery using self-derived peptides that can be developed to target the structures of any essential bacterial proteins.-Zhan, J., Jia, H., Semchenko, E. A., Bian, Y., Zhou, A. M., Li, Z., Yang, Y., Wang, J., Sarkar, S., Totsika, M., Blanchard, H., Jen, F. E.-C., Ye, Q., Haselhorst, T., Jennings, M. P., Seib, K. L., Zhou, Y. Self-derived structure-disrupting peptides targeting methionine aminopeptidase in pathogenic bacteria: a new strategy to generate antimicrobial peptides.

Original languageEnglish (US)
Pages (from-to)2095-2104
Number of pages10
JournalFASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume33
Issue number2
DOIs
StatePublished - Feb 1 2019

Fingerprint

Aminopeptidases
Methionine
Bacteria
Peptides
Pharmaceutical Preparations
Anti-Bacterial Agents
Bacterial Proteins
Neisseria gonorrhoeae
Drug and Narcotic Control
Pathogens
Enzymes
Bacterial Infections
Escherichia coli
Cause of Death
Emergencies
Epithelial Cells
Health

Keywords

  • antibiotic resistance
  • protein-specific denaturation

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Self-derived structure-disrupting peptides targeting methionine aminopeptidase in pathogenic bacteria : a new strategy to generate antimicrobial peptides. / Zhan, Jian; Jia, Husen; Semchenko, Evgeny A.; Bian, Yunqiang; Zhou, Amy M.; Li, Zhixiu; Yang, Yuedong; Wang, Jihua; Sarkar, Sohinee; Totsika, Makrina; Blanchard, Helen; Jen, Freda E.C.; Ye, Qizhuang; Haselhorst, Thomas; Jennings, Michael P.; Seib, Kate L.; Zhou, Yaoqi.

In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Vol. 33, No. 2, 01.02.2019, p. 2095-2104.

Research output: Contribution to journalArticle

Zhan, J, Jia, H, Semchenko, EA, Bian, Y, Zhou, AM, Li, Z, Yang, Y, Wang, J, Sarkar, S, Totsika, M, Blanchard, H, Jen, FEC, Ye, Q, Haselhorst, T, Jennings, MP, Seib, KL & Zhou, Y 2019, 'Self-derived structure-disrupting peptides targeting methionine aminopeptidase in pathogenic bacteria: a new strategy to generate antimicrobial peptides', FASEB journal : official publication of the Federation of American Societies for Experimental Biology, vol. 33, no. 2, pp. 2095-2104. https://doi.org/10.1096/fj.201700613RR
Zhan, Jian ; Jia, Husen ; Semchenko, Evgeny A. ; Bian, Yunqiang ; Zhou, Amy M. ; Li, Zhixiu ; Yang, Yuedong ; Wang, Jihua ; Sarkar, Sohinee ; Totsika, Makrina ; Blanchard, Helen ; Jen, Freda E.C. ; Ye, Qizhuang ; Haselhorst, Thomas ; Jennings, Michael P. ; Seib, Kate L. ; Zhou, Yaoqi. / Self-derived structure-disrupting peptides targeting methionine aminopeptidase in pathogenic bacteria : a new strategy to generate antimicrobial peptides. In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2019 ; Vol. 33, No. 2. pp. 2095-2104.
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AU - Zhan, Jian

AU - Jia, Husen

AU - Semchenko, Evgeny A.

AU - Bian, Yunqiang

AU - Zhou, Amy M.

AU - Li, Zhixiu

AU - Yang, Yuedong

AU - Wang, Jihua

AU - Sarkar, Sohinee

AU - Totsika, Makrina

AU - Blanchard, Helen

AU - Jen, Freda E.C.

AU - Ye, Qizhuang

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