Peptides step up

Bringing antimicrobial peptides in for the kill

New screening platforms and synthetic approaches could finally solve some of the longstanding hurdles to turning antimicrobial peptides into therapeutic candidates to combat antibacterial resistance, overcoming their history of limited clinical efficacy, systemic toxicity and high cost.

The advances come from platforms that move beyond the search for naturally occurring peptides that has been common in the field, with systems to increase chemical space, employ unnatural polymers or combine different elements to engineer new structures.

Eukaryotes and bacteria produce a wealth of peptides to combat pathogens and competing strains, respectively. The molecules have potential for broad-spectrum activity with few avenues for resistance because their killing mechanisms are based on biophysically disrupting membranes or binding large swaths of intracellular proteins or nucleic acids.

For example, most antimicrobial peptides are amphiphilic, containing both a hydrophobic region and a positively charged hydrophilic region, which enables them to kill bacteria by disrupting their negatively charged membranes, or by permeating the membranes to target intracellular machinery. But neutrally charged eukaryotic cell membranes are spared.

The peptides also modulate host inflammatory and immune activity, and can rev up immune responses to the pathogen.

However, only one class of antimicrobial peptides, polymyxins, has produced marketed therapeutics that aren’t topical, and the molecules have neurotoxic and nephrotoxic side effects that limit use to last resort cases. Topical versions of polymyxins and another antimicrobial peptide, gramcidin, are also on the market.

In the last two years, BioCentury has documented eight new antimicrobial peptides in the Distillery section, which tracks translational publications with commercial potential (see

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