Antibiotics are our best weapons against bacterial infections. However, their excessive use has accelerated the emergence of multidrug resistance (MDR), and we are quickly running out of useful drugs. This is particularly a concern for Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), where off-target destruction of the host lung microbiome by broad-spectrum antibiotics exacerbates disease severity and increases the incidence of MDR. Here, we present a de novo designed tryptophan-rich peptide capable of rapidly and selectively killing Mtb, while being remarkably biocompatible towards model commensal flora and human cells. Circular dichroism spectroscopy and electron microscopy reveal that under pathophysiological conditions this narrow-spectrum peptide, named myco-membrane associated disruption 1 (MAD1) sequence, assembles into monomorphic fibrils that are stabilized by an intermolecular tryptophan zipper. Biophysical studies using model membranes and mycobacterial cultures demonstrate that MAD1 preferentially interacts with the unique mycolic-acid rich surface of Tuberculosis pathogens to elicit rapid membrane depolarization. Conversely, MAD1 is relatively benign towards other gram-positive and gram-negative microbes with mycolic acid-deficient cell walls. Together with the unusual tryptophan-rich nature of mycobacterial transmembrane proteins, this suggests that tryptophan-zippered MAD1 nano-assemblies may mimic myco-membrane proteins to act as a biologic ‘Trojan horse’; enabling their selective integration into, and disruption of, the mycobacterial cell wall (Fig. 1). This work has the potential to open new opportunities for the rational design of pathogen-specific antimicrobial peptides via membrane-protein biomimicry, and advance the development of narrow-spectrum biotherapeutics to combat antimicrobial resistance.

Tryptophan-zippered ‘Trojan horse’ peptides with anti-tuberculosis specific activity

2019 Fall National Meeting

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