<p>Precision antimicrobials that can kill pathogens without damaging host
commensals hold potential to cure disease without antibiotic-associated
dysbiosis. Here we report the <i>de novo</i> 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 <i>Mycobacterium tuberculosis</i> (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.</p>
<p>Precision antimicrobials that can kill pathogens without damaging host
commensals hold potential to cure disease without antibiotic-associated
dysbiosis. Here we report the <i>de novo</i> 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 <i>Mycobacterium tuberculosis</i> (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.</p>
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