| Summary: | The Gram-negative <i>Elizabethkingia</i> express multiple antibiotic resistance and cause severe opportunistic infections. Vancomycin is commonly used to treat Gram-positive infections and has also been used to treat <i>Elizabethkingia</i> infections, even though Gram-negative organisms possess a vancomycin permeability barrier. <i>Elizabethkingia anophelis</i> appeared relatively vancomycin-susceptible and challenge with this drug led to morphological changes indicating cell lysis. In stark contrast, vancomycin growth challenge revealed that <i>E. anophelis</i> populations refractory to vancomycin emerged. In addition, <i>E. anophelis</i> vancomycin-selected mutants arose at high frequencies and demonstrated elevated vancomycin resistance and reduced susceptibility to other antimicrobials. All mutants possessed a SNP in a gene (<i>vsr1</i> = vancomycin-susceptibility regulator 1) encoding a PadR family transcriptional regulator located in the putative operon <i>vsr1-ORF551</i>, which is conserved in other <i>Elizabethkingia</i> spp as well. This is the first report linking a <i>padR</i> homologue (<i>vsr1</i>) to antimicrobial resistance in a Gram-negative organism. We provide evidence to support that <i>vsr1</i> acts as a negative regulator of <i>vsr1-ORF551</i> and that <i>vsr1-ORF551</i> upregulation is observed in vancomycin-selected mutants. Vancomycin-selected mutants also demonstrated reduced cell length indicating that cell wall synthesis is affected. ORF551 is a membrane-spanning protein with a small phage shock protein conserved domain. We hypothesize that since vancomycin-resistance is a function of membrane permeability in Gram-negative organisms, it is likely that the antimicrobial resistance mechanism in the vancomycin-selected mutants involves altered drug permeability.
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