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Determinants of Antibacterial Spectrum and Resistance Potential of the Elongation Factor G Inhibitor Argyrin B in Key Gram-Negative Pathogens.

Abstract：

:Argyrins are natural products with antibacterial activity against Gram-negative 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 μg/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 μg/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 argyrin-insensitive 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.

journal_name

Antimicrob Agents Chemother

journal_title

Antimicrobial agents and chemotherapy

authors

Jones AK,Woods AL,Takeoka KT,Shen X,Wei JR,Caughlan RE,Dean CR

doi

10.1128/AAC.02400-16

subject

Has Abstract

pub_date

2017-03-24 00:00:00

issue

eissn

0066-4804

issn

1098-6596

pii

AAC.02400-16

journal_volume

pub_type

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Determinants of Antibacterial Spectrum and Resistance Potential of the Elongation Factor G Inhibitor Argyrin B in Key Gram-Negative Pathogens.