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

Andrew W. Simonson; Agustey S. Mongia; Matthew R. Aronson; John N. Alumasa; Dennis C. Chan; Atip Lawanprasert; Michael D. Howe; Adam Bolotsky; Tapas K. Mal; Christy George; Aida Ebrahimi; Anthony D. Baughn; Elizabeth A. Proctor; Kenneth C. Keiler; Scott H. Medina

doi:10.1038/s41551-020-00665-x

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

Andrew W. Simonson, Agustey S. Mongia, Matthew R. Aronson, John N. Alumasa, Dennis C. Chan, Atip Lawanprasert, Michael D. Howe, Adam Bolotsky, Tapas K. Mal, Christy George, Aida Ebrahimi, Anthony D. Baughn, Elizabeth A. Proctor, Kenneth C. Keiler, Scott H. Medina

Microbiology

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	467-480
Number of pages	14
Journal	Nature Biomedical Engineering
Volume	5
Issue number	5
Early online date	Jan 4 2021
DOIs	https://doi.org/10.1038/s41551-020-00665-x
State	Published - May 2021

Bibliographical note

Funding Information:
We thank the Penn State Microscopy and Cytometry Facility, University Park, PA for assistance with confocal and electron microscopy; the Penn State X-Ray Crystallography Facility, University Park, PA for use of the CD spectrophotometer; the Penn State NMR Facility, University Park, PA for use of NMR instrumentation. Funding for this research was provided by the Penn State Institute of Energy and the Environment Human Health and the Environment Seed Grant awarded to S.H.M. This work was also supported by NIH grant number AI123146 to A.D.B. A.W.S. was supported by funds from the Penn State Graduate Research Fellowship.

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.

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Simonson, A. W., Mongia, A. S., Aronson, M. R., Alumasa, J. N., Chan, D. C., Lawanprasert, A., Howe, M. D., Bolotsky, A., Mal, T. K., George, C., Ebrahimi, A., Baughn, A. D., Proctor, E. A., Keiler, K. C., & Medina, S. H. (2021). Pathogen-specific antimicrobials engineered de novo through membrane-protein biomimicry. Nature Biomedical Engineering, 5(5), 467-480. https://doi.org/10.1038/s41551-020-00665-x

Simonson, AW, Mongia, AS, Aronson, MR, Alumasa, JN, Chan, DC, Lawanprasert, A, Howe, MD, Bolotsky, A, Mal, TK, George, C, Ebrahimi, A, Baughn, AD, Proctor, EA, Keiler, KC & Medina, SH 2021, 'Pathogen-specific antimicrobials engineered de novo through membrane-protein biomimicry', Nature Biomedical Engineering, vol. 5, no. 5, pp. 467-480. https://doi.org/10.1038/s41551-020-00665-x

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abstract = "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{\textquoteright}s channel-forming membrane proteins. By exploiting physical and structural vulnerabilities within the pathogen{\textquoteright}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.",

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

Abstract

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