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Antimicrob Agents Chemother. 2017 May 24;61(6). pii: e02635-16. doi: 10.1128/AAC.02635-16. Print 2017 Jun.

A New Natural Product Analog of Blasticidin S Reveals Cellular Uptake Facilitated by the NorA Multidrug Transporter.

Author information

1
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
2
Department of Biochemistry, McGill University, Montreal, Canada.
3
University of Minnesota-Twin Cities, Bioinformatics and Computational Biology Program, Minneapolis, Minnesota, USA.
4
NIH Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
5
University of Minnesota-Twin Cities, Department of Computer Science and Engineering, Minneapolis, Minnesota, USA.
6
Great Lakes Bioenergy Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
7
Genomics Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
8
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA caroleb@mail.nih.gov.

Abstract

The permeation of antibiotics through bacterial membranes to their target site is a crucial determinant of drug activity but in many cases remains poorly understood. During screening efforts to discover new broad-spectrum antibiotic compounds from marine sponge samples, we identified a new analog of the peptidyl nucleoside antibiotic blasticidin S that exhibited up to 16-fold-improved potency against a range of laboratory and clinical bacterial strains which we named P10. Whole-genome sequencing of laboratory-evolved strains of Staphylococcus aureus resistant to blasticidin S and P10, combined with genome-wide assessment of the fitness of barcoded Escherichia coli knockout strains in the presence of the antibiotics, revealed that restriction of cellular access was a key feature in the development of resistance to this class of drug. In particular, the gene encoding the well-characterized multidrug efflux pump NorA was found to be mutated in 69% of all S. aureus isolates resistant to blasticidin S or P10. Unexpectedly, resistance was associated with inactivation of norA, suggesting that the NorA transporter facilitates cellular entry of peptidyl nucleosides in addition to its known role in the efflux of diverse compounds, including fluoroquinolone antibiotics.

KEYWORDS:

antibiotic resistance; chemical genomics; natural products; transporters

PMID:
28373194
PMCID:
PMC5444127
DOI:
10.1128/AAC.02635-16
[Indexed for MEDLINE]
Free PMC Article

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