Identifying producers of antibacterial compounds by screening for antibiotic resistance.
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.
Department of Biochemistry and Biomedical Sciences, M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
Maulik N
MN
Thaker
Wenliang
W
Wang
Peter
P
Spanogiannopoulos
Nicholas
N
Waglechner
Andrew M
AM
King
Ricardo
R
Medina
Gerard D
GD
Wright
D039903:Actinobacteria / Q000737:chemistry / Q000187:drug effects; D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D053898:Biosynthetic Pathways / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004352:Drug Resistance, Microbial / Q000187:drug effects; D006020:Glycopeptides / Q000096:biosynthesis / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D010802:Phylogeny; D015203:Reproducibility of Results; D012293:Rifampin / Q000737:chemistry / Q000494:pharmacology; D014640:Vancomycin / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D006020:Glycopeptides; D014640:Vancomycin; D012293:Rifampin