Assembly and clustering of natural antibiotics guides target identification

Chad W Johnston; Michael A Skinnider; Chris A Dejong; Philip N Rees; Gregory M Chen; Chelsea G Walker; Shawn French; Eric D Brown; János Bérdy; Dennis Y Liu; Nathan A Magarvey

doi:10.1038/nchembio.2018

Assembly and clustering of natural antibiotics guides target identification

Nat Chem Biol. 2016 Apr;12(4):233-9. doi: 10.1038/nchembio.2018. Epub 2016 Feb 1.

Authors

Chad W Johnston^{1

2}, Michael A Skinnider^{1

2}, Chris A Dejong^{1

2}, Philip N Rees^{1

2}, Gregory M Chen^{1

2}, Chelsea G Walker^{1

2}, Shawn French¹, Eric D Brown¹, János Bérdy³, Dennis Y Liu^{1

2}, Nathan A Magarvey^{1

2}

Affiliations

¹ Department of Biochemistry &Biomedical Sciences, M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
² Department of Chemistry &Chemical Biology, McMaster University, Hamilton, Ontario, Canada.
³ Eötvös Loránd University, IVAX Drug Research Institute Ltd., Budapest, Hungary.

PMID: 26829473
DOI: 10.1038/nchembio.2018

Abstract

Antibiotics are essential for numerous medical procedures, including the treatment of bacterial infections, but their widespread use has led to the accumulation of resistance, prompting calls for the discovery of antibacterial agents with new targets. A majority of clinically approved antibacterial scaffolds are derived from microbial natural products, but these valuable molecules are not well annotated or organized, limiting the efficacy of modern informatic analyses. Here, we provide a comprehensive resource defining the targets, chemical origins and families of the natural antibacterial collective through a retrobiosynthetic algorithm. From this we also detail the directed mining of biosynthetic scaffolds and resistance determinants to reveal structures with a high likelihood of having previously unknown modes of action. Implementing this pipeline led to investigations of the telomycin family of natural products from Streptomyces canus, revealing that these bactericidal molecules possess a new antibacterial mode of action dependent on the bacterial phospholipid cardiolipin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents / biosynthesis
Anti-Bacterial Agents / isolation & purification
Anti-Bacterial Agents / pharmacology*
Biological Products / isolation & purification
Biological Products / pharmacology*
Biosynthetic Pathways
Cardiolipins / biosynthesis*
Cardiolipins / genetics
Colony Count, Microbial
Databases, Genetic
Drug Resistance, Bacterial / drug effects
Drug Resistance, Bacterial / genetics
Gram-Positive Bacteria / drug effects*
Gram-Positive Bacteria / genetics
Gram-Positive Bacteria / growth & development
Gram-Positive Bacteria / metabolism
Microbial Sensitivity Tests
Multigene Family
Peptides / genetics
Peptides / isolation & purification
Peptides / pharmacology*
Streptomyces / metabolism*
Web Browser

Substances

Anti-Bacterial Agents
Biological Products
Cardiolipins
Peptides
telomycin

Associated data

PubChem-Substance/283538288
PubChem-Substance/283538289
PubChem-Substance/283538290
PubChem-Substance/283538291
PubChem-Substance/283538292
PubChem-Substance/283538293
PubChem-Substance/283538294
PubChem-Substance/283538295
PubChem-Substance/283538296
PubChem-Substance/283538297

Grants and funding

Canadian Institutes of Health Research/Canada