Pathogen-Specific De Novo Antimicrobials Engineered Through Membrane Porin Biomimicry

Precision antimicrobials that can kill pathogens without damaging host commensals hold potential to cure disease without antibiotic-associated dysbiosis. Here we report the de novo design of host defense peptides that have been rationally engineered to precisely target specific pathogens by mimicking key molecular features of the target microbe’s unique channel-forming membrane proteins, or porins. This biomimetic strategy exploits physical and structural motifs of the pathogen envelope, rather than targeting resistance-susceptible protein biochemical pathways, to construct fast-acting precision bacteriolytics. Utilizing this approach, we design an antitubercular 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 commensals or host tissue. These mycomembrane-templated mechanisms are rapid and synergistically enhance the potency of antibiotics that otherwise poorly diffuse across the rigid Mtb envelope, particularly those that exploit porins for antimycobacterial activity. This new porin-mimetic paradigm may serve as a conceptual basis for the directed design of new narrow-spectrum antimicrobial scaffolds.