Waking a Silent Gene Cluster Yields 'Biffamycin A,' a Minimal Glycopeptide Antibiotic

Researchers at the Astbury Centre for Structural Molecular Biology at the University of Leeds in the United Kingdom, the John Innes Centre and elsewhere discovered a new glycopeptide antibiotic (GPA), biffamycin A, and analysed its biosynthesis. Most clinical antibiotics have come from bacterial natural products, but industry has turned away from this resource because known compounds keep being rediscovered. Cheaper genome sequencing and bioinformatics tools are bringing renewed interest by revealing biosynthetic pathways that are not expressed in the laboratory.

A minimal four-amino-acid GPA with unprecedented building blocks

The researchers engineered the expression of a silent biosynthetic gene cluster carried by Streptomyces albidoflavus isolated from the environment, and isolated the compound guided by bioinformatic predictions. Biffamycin A is the smallest glycotetrapeptide among known GPAs, and it carries unprecedented building blocks: 5-chloro-4-methoxy tryptophan and 3-hydroxy-D-lysine attached to mannose. It showed antibacterial activity against mycobacteria and staphylococci, and it also acted on methicillin- and vancomycin-resistant Staphylococcus aureus.

It is significant that a new scaffold has been obtained within the GPA class, represented by vancomycin. However, these are in vitro antibacterial activity results, and efficacy in animal infection models and toxicity have not been confirmed.