1.D.144. The Synthetic Mycobacterium-specific Pore-forming Disruption-1 Peptide (MAD1) Family
Precision antimicrobials should kill pathogens without damaging commensal bacteria in the host, and thereby cure disease without antibiotic-associated dysbiosis. Simonson et al. 2021 reported 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 outer membrane proteins, modeled after MspA (TC# 1.B.24.1.1) of Mycobacteria. By exploiting physical and structural vulnerabilities within the pathogen's cellular envelope, Simonson et al. 2021 designed a 13 residue peptide sequence (MAD1, KRWHWWRRHWVVW-NH2) that undergoes instructed tryptophan-zippered assembly within the mycolic acid-rich outer membrane of Mycobacterium tuberculosis. It specifically kills 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 (Simonson et al. 2021).