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

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.

• Authors: 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
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 33 Issue 2 Pg. 2095-2104 (02 2019) ISSN: 1530-6860 [Electronic] United States
• PMID: 30260702 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Antimicrobial Cationic Peptides
• Methionine
• Aminopeptidases

Topics

• Aminopeptidases (antagonists & inhibitors)
• Anti-Bacterial Agents (pharmacology)
• Antimicrobial Cationic Peptides (pharmacology)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Cervix Uteri (drug effects, metabolism, microbiology)
• Drug Resistance, Multiple, Bacterial
• Female
• Gonorrhea (drug therapy, microbiology)
• Humans
• Methionine (metabolism)
• Microbial Sensitivity Tests
• Neisseria gonorrhoeae (drug effects, enzymology)