Identifying producers of antibacterial compounds by screening for antibiotic resistance

• Published in: Nature biotechnology Vol. 31; no. 10; pp. 922 - 927
• Main Authors: Thaker, Maulik N, Wang, Wenliang, Spanogiannopoulos, Peter, Waglechner, Nicholas, King, Andrew M, Medina, Ricardo, Wright, Gerard D
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2013; Nature Publishing Group
• Subjects: 631/154/1435; 631/154/349; Actinobacteria - chemistry; Actinobacteria - drug effects; Agriculture; Anti-Bacterial Agents - biosynthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - isolation & purification; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibacterial materials; Antibiotic resistance; Antibiotics; Antimicrobial agents; Bioinformatics; Biomedical Engineering/Biotechnology; Biomedicine; Biosynthesis; Biosynthetic Pathways - drug effects; Biotechnology; Drug Evaluation, Preclinical - methods; Drug resistance; Drug resistance in microorganisms; Drug Resistance, Microbial - drug effects; Glycopeptides; Glycopeptides - biosynthesis; Glycopeptides - chemistry; Glycopeptides - isolation & purification; Glycopeptides - pharmacology; Life Sciences; Microbiology; Microorganisms; Natural products; Peptides; Phylogeny; Properties; Reproducibility of Results; Rifampin - chemistry; Rifampin - pharmacology; Scaffolds; Screening; Synthetic biology; Vancomycin - chemistry; Vancomycin - isolation & purification; Vancomycin - pharmacology; United States
• DOI: 10.1038/nbt.2685
• ISSN: 1087-0156; 1546-1696

Selecting for microorganisms resistant to known antibiotics enables discovery of strains that produce structurally related compounds. Microbially derived natural products are major sources of antibiotics and other medicines, but discovering new antibiotic scaffolds and increasing the chemical diversity of existing ones are formidable challenges. We have designed a screen to exploit the self-protection mechanism of antibiotic producers to enrich microbial libraries for producers of selected antibiotic scaffolds. Using resistance as a discriminating criterion we increased the discovery rate of producers of both glycopeptide and ansamycin antibacterial compounds by several orders of magnitude in comparison with historical hit rates. Applying a phylogeny-based screening filter for biosynthetic genes enabled the binning of producers of distinct scaffolds and resulted in the discovery of a glycopeptide antibacterial compound, pekiskomycin, with an unusual peptide scaffold. This strategy provides a means to readily sample the chemical diversity available in microbes and offers an efficient strategy for rapid discovery of microbial natural products and their associated biosynthetic enzymes.