Antimicrobials Inspired by Nonribosomal Peptide Synthetase Gene Clusters

Bacterial culture broth extracts
have been the starting point for
the development of numerous therapeutics. However, only a small fraction
of bacterial biosynthetic diversity is accessible using this strategy.
Here, we apply a discovery approach that bypasses the culturing step
entirely by bioinformatically predicting small molecule structures
from the primary sequences of the biosynthetic gene clusters. These
structures are then chemically synthesized to give synthetic-bioinformatic
natural products (syn-BNPs). Using this approach, we screened syn-BNPs
inspired by nonribosomal peptide synthetases against microbial pathogens,
and discovered an antibiotic for which no resistance could be identified
and an antifungal agent with activity against diverse fungal pathogens.