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HEXIM1 Peptide Exhibits Antimicrobial Activity Against Antibiotic Resistant Bacteria Through Guidance of Cell Penetrating Peptide

From left: Ong Han Kee, Dr Jimmy Chao, Ho Pooi Leng, Dr Dave Ow


Pooi Leng Ho 1#, Han Kee Ong 2#, Jeanette Teo 3, Dave Siak-Wei Ow 1, and Sheng-Hao Chao 2,4

1 Microbial Cells and 2 Expression Engineering Groups, Bioprocessing Technology institute, Agency for Science, Technology and Research (A*STAR), Singapore
3 Department of Laboratory medicine, National University Hospital, Singapore
4 Department of Microbiology and Immunology, National University of Singapore, Singapore
# These authors have contributed equally to this work

Published in Frontiers in Microbiology 2019 10: 203 (Online Version)



Antibiotics are crucial medicines used for treating bacterial infections. Unfortunately, due to overuse, underuse and misuse, bacterial resistance to antibiotics are emerging and spreading rapidly. Antibiotic resistance has significantly decreased antibiotics’ treatment efficiency, creating a need for alternative antimicrobials against antibiotic resistant bacteria. Antimicrobial peptides are small molecules that can be found in natural immune system as part of defence mechanism against invading pathogens. They either disrupt bacteria cell membrane or its intracellular mechanisms which leads to cell death. The chances of developing resistance against antimicrobial peptides are low because microbes will require significant changes to evade the peptides. Thus gaining more attention for development as therapeutic candidates against antibiotic resistant bacteria.

Some anticancer peptides are also cytotoxic against microbial cells, possibly due to similar peptide characteristics and the conserved cellular pathways between bacterial and mammalian cells. The HEXIM1 BR is an anticancer peptide that BTI has worked with. The peptide displayed a few typical antimicrobial peptide characteristics - multiple lysine and arginine residues and is highly positively charged. Hence in this study, we looked into the antimicrobial activities of HEXIM1 BR peptide fused with a cell penetrating peptide. We found that the HEXIM1 BR peptide and its derivative, BR-RRR12, displayed potent antimicrobial activities against several antibiotic resistant bacteria which were classified as critical ‘superbugs’ by WHO. When tested for cytotoxicity of peptides on human cell line, HaCaT, negligible effect was seen at bactericidal dosages. Membrane permeabilizing antimicrobial peptides typically cause instantaneous cell death. However, HEXIM1 BR peptides were observed to have delayed killing effect, suggesting a different antimicrobial mechanism might be utilized. Using an in vitro translation system based on E. coli lysates, we found that HEXIM1 BR peptides blocked bacterial translation. Additional studies, which are not reported in our paper, showed presence of propidium iodide detected in peptide treated cells, signifying that cell permeability may be compromised. This raises the possibility that multiple mechanisms may be utilized by the HEXIM1 BR peptides for its antimicrobial activity. Taken together, these results indicate that HEXIM1 BR peptides are potential novel antimicrobial peptides with potent inhibitory activity against antibiotic resistant ‘superbugs’.

Figure 1. HEXIM1 BR peptides and their antimicrobial activities. (A) Schematic overview of Pen-HEXIM1 BR fusion peptides. (B) Inhibitory and bactericidal activity of peptides on selected susceptible and antibiotic-resistant superbugs.


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