Synthetic antibiotics with novel mechanism of action discovered

  • Luther A, et al.
  • Nature
  • 23 Oct 2019

  • curated by Priscilla Lynch
  • Medical News
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A novel family of synthetic antibiotics that possess broad-spectrum anti-Gram-negative antimicrobial activity has been discovered.

A study published in Nature reports the discovery and characterisation of the new antibiotics, which are based on scaffolds derived from natural products. The chimeric antibiotics contain a β-hairpin peptide macrocycle linked to the macrocycle found in the polymyxin and colistin family of natural products.

The antibiotics are bactericidal and have a mechanism of action that involves binding to both lipopolysaccharide and the main component (BamA) of the β-barrel folding complex (BAM) that is required for the folding and insertion of β-barrel proteins into the outer membrane of Gram-negative bacteria. After targeting this essential outer membrane protein, the antibiotics destroy the integrity of the bacterial membranes and the cells burst.

The researchers report that extensively optimised derivatives of the novel antibiotics show potent activity against multidrug-resistant pathogens, including all of the Gram-negative members of the ESKAPE pathogens. These derivatives also show favourable drug properties and overcome colistin resistance, both in vitro and in vivo, they noted.

The lead antibiotic candidate is currently in preclinical toxicology studies.

The discovery has the potential to address life-threatening infections by Gram-negative pathogens, and thus to resolve a considerable unmet medical need, the researchers said.