Pathogen-specific antimicrobials engineered de novo through membrane-protein biomimicry

Pathogen-specific antimicrobials engineered de novo through membrane-protein biomimicry

Precision antimicrobials aim to kill pathogens without damaging commensal bacteria in the host, and thereby cure disease without antibiotic-associated dysbiosis. Here we report the de novo design of a synthetic host defence peptide that targets a specific pathogen by mimicking key molecular features...

Full description

Saved in:
Bibliographic Details
Published in:Nature biomedical engineering Vol. 5; no. 5; pp. 467 - 480
Main Authors: Simonson, Andrew W., Mongia, Agustey S., Aronson, Matthew R., Alumasa, John N., Chan, Dennis C., Lawanprasert, Atip, Howe, Michael D., Bolotsky, Adam, Mal, Tapas K., George, Christy, Ebrahimi, Aida, Baughn, Anthony D., Proctor, Elizabeth A., Keiler, Kenneth C., Medina, Scott H.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 01-05-2021
Nature Publishing Group
Subjects:
13/106
14/19
14/28
14/34
38
631/154/51
631/326/22
631/92/611
692/4017
82/58
82/6
Antibiotics
Antiinfectives and antibacterials
Antimicrobial agents
Antimicrobial peptides
Bacteria
Biomedical and Life Sciences
Biomedical Engineering/Biotechnology
Biomedicine
Biomimetics
Cellular structure
Dysbacteriosis
Membrane proteins
Membranes
Mimicry
Molecular structure
Mycobacterium tuberculosis
Pathogens
Peptides
Proteins
Toxicity
Tryptophan
Tuberculosis
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Precision antimicrobials aim to kill pathogens without damaging commensal bacteria in the host, and thereby cure disease without antibiotic-associated dysbiosis. Here we report the de novo design of a synthetic host defence peptide that targets a specific pathogen by mimicking key molecular features of the pathogen’s channel-forming membrane proteins. By exploiting physical and structural vulnerabilities within the pathogen’s cellular envelope, we designed a peptide sequence that undergoes instructed tryptophan-zippered assembly within the mycolic acid-rich outer membrane of Mycobacterium tuberculosis to specifically kill the pathogen without collateral toxicity towards lung commensal bacteria or host tissue. These mycomembrane-templated assemblies elicit rapid mycobactericidal activity and enhance the potency of antibiotics by improving their otherwise poor diffusion across the rigid M. tuberculosis envelope with respect to agents that exploit transmembrane protein channels for antimycobacterial activity. This biomimetic strategy may aid the design of other narrow-spectrum antimicrobial peptides. Mimicking the molecular architecture of channel-forming membrane proteins of a target microbe can be used to design host defence peptides that specifically target a particular pathogen, as shown here for Mycobacterium tuberculosis .
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
A.W.S. and S.H.M. conceived the hypothesis, designed the experiments, and wrote the manuscript. A.W.S., A.S.M., M.R.A., J.A., D.C.C., A.L., M.D.H., A.B., T.K.M., C.G., A.E., A.D.B., E.A.P. and K.C.K designed and performed the experiments, analyzed the results and contributed to writing of the manuscript.
Author contributions
ISSN:2157-846X
2157-846X
DOI:10.1038/s41551-020-00665-x