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

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


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 languageEnglish (US)
Pages (from-to)467-480
Number of pages14
JournalNature Biomedical Engineering
Issue number5
StatePublished - May 2021

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Bioengineering
  • Medicine (miscellaneous)
  • Biomedical Engineering
  • Computer Science Applications


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