A new natural product antibiotic reveals cellular uptake facilitated by the NorA multidrug efflux protein

Authors

• JR Davison
• KM Lohith
• S Mandadapu
• K Bobyk
• X Wang
• J Piotrowski
• HE Smith
• CA Bewley

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 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 the 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 an inversion of its typical role in the efflux of diverse compounds including fluoroquinolone antibiotics.

Scientific Focus Area: Chemical Biology

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