Self-derived structure-disrupting peptides targeting methionine aminopeptidase in pathogenic bacteria: a new strategy to generate antimicrobial peptides

What is it about?

The fast spread of multidrug resistant bacteria is a global health emergency. In the absence of new drugs, common infections could become untreatable this century. Synthetic compounds resulting from high-throughput screening and rational drug design that started in the 1990s did not lead to significant discoveries of new antibiotics as was hoped, mainly due to off-target toxic effects and/or an inability to penetrate bacterial cells. The rapid emergence and global spread of drug resistance demands a new approach for developing novel antibiotics that has a high success rate. Here we developed a combined computational modeling and experimental approach to identify self-targeting peptides that disrupt structures of essential bacterial proteins. Drugs are commonly designed to inhibit the functional or active site of a target protein, which is prone to mutate (i.e. develop resistance) without significant damage to protein function. Targeting active sites also carries the complication of similarities between bacterial and host enzyme active sites, and thereby selective toxicity. In contrast, a protein's core structure, once disrupted, should be harder to overcome by suppressor mutations, because mutations to the protein core would be more likely to destabilize the entire protein structure and result in a complete loss of activity. Here, we demonstrated the concept of structure disrupting peptides as antibiotics without resistance by using the peptide segment of Helix 3 of the methionine aminopeptidase of Escherichia coli.

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