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Determinants of antibacterial spectrum and resistance potential of the elongation factor G inhibitor argyrin B in key Gram negative pathogens.

Jones, Adriana and Woods, Angela and Takeoka, Ken and Shen, Xiaoyu and Wei, Jun-Rong and Caughlan, Ruth and Dean, Charles (2017) Determinants of antibacterial spectrum and resistance potential of the elongation factor G inhibitor argyrin B in key Gram negative pathogens. Antimicrobial agents and chemotherapy, 61 (4). ISSN 1098-6596

Abstract

Argyrins are natural products with antibacterial activity against Gramnegative
pathogens, such as Pseudomonas aeruginosa, Burkholderia multivorans, and
Stenotrophomonas maltophilia. We previously showed that argyrin B targets elongation
factor G (FusA). Here, we show that argyrin B activity against P. aeruginosa
PAO1 (MIC � 8 �g/ml) was not affected by deletion of the MexAB-OprM,
MexXY-OprM, MexCD-OprJ, or MexEF-OprN efflux pump. However, argyrin B induced
expression of MexXY, causing slight but reproducible antagonism with the
MexXY substrate antibiotic ciprofloxacin. Argyrin B activity against Escherichia coli
increased in a strain with nine tolC efflux pump partner genes deleted. Complementation
experiments showed that argyrin was effluxed by AcrAB, AcrEF, and
MdtFX. Argyrin B was inactive against Acinetobacter baumannii. Differences between
A. baumannii and P. aeruginosa FusA proteins at key residues for argyrin B
interaction implied that natural target sequence variation impacted antibacterial
activity. Consistent with this, expression of the sensitive P. aeruginosa FusA1 protein
in A. baumannii conferred argyrin susceptibility, whereas resistant variants
did not. Argyrin B was active against S. maltophilia (MIC � 4 �g/ml). Spontaneous
resistance occurred at high frequency in the bacterium (circa 10�7), mediated
by mutational inactivation of fusA1 rather than by amino acid substitutions
in the target binding region. This strongly suggested that resistance occurred at
high frequency through loss of the sensitive FusA1, leaving an alternate argyrininsensitive
elongation factor. Supporting this, an additional fusA-like gene (fusA2)
is present in S. maltophilia that was strongly upregulated in response to mutational
loss of fusA1.

Item Type: Article
Keywords: Argyrin, elongation factor G, natural products, antibacterial, resistance
Date Deposited: 29 Mar 2017 00:45
Last Modified: 29 Mar 2017 00:45
URI: https://oak.novartis.com/id/eprint/31110

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