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

Precision antimicrobials aim to kill pathogens without damaging commensal bacteria in the host, and thus to 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 (Mtb) 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 Mtb 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.