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Mapping the efficacy and mode of action of ethylzingerone [4-(3-ethoxy-4-hydroxyphenyl) butan-2-one] as an active agent against Burkholderia bacteria

Rushton, Laura, Khodr, Ahmad, Menard-Szczebara, Florence, Maillard, Jean-Yves, Cupferman, Sylvie and Mahenthiralingam, Eshwar 2020. Mapping the efficacy and mode of action of ethylzingerone [4-(3-ethoxy-4-hydroxyphenyl) butan-2-one] as an active agent against Burkholderia bacteria. Applied and Environmental Microbiology 86 (19) , e01808-20. 10.1128/AEM.01808-20
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Abstract

Burkholderia cepacia complex (Bcc) bacteria are intrinsically antimicrobial-resistant opportunistic pathogens and key risk species in the contamination of nonfood industrial products. New agents and formulations to prevent growth of Burkholderia in home care (cleaning agents) and personal-care (cosmetics and toiletries) products are required. We characterized how ethylzingerone [4-(3-ethoxy-4-hydroxyphenyl) butan-2-one] (HEPB) acts as a preservative with activity against Burkholderia species encountered in industry. Burkholderia (n = 58) and non-Burkholderia (n = 7) bacteria were screened for susceptibility to HEPB, and its mode of action and resistance were determined for a model Burkholderia vietnamiensis strain using transposon mutagenesis, transcriptomics, and genome resequencing analysis. The susceptibility of Burkholderia spp. to HEPB (MIC = 0.45% ± 0.11% [wt/vol]; MBC = 0.90% ± 0.3% [wt/vol]) was characterized, with limited inter- and intraspecies differences. HEPB (1% [wt/vol]) was rapidly bactericidal, producing a 6-log reduction in viability within 4 h. Spontaneous resistance to HEPB did not develop, but transient phenotypes with altered growth characteristics and susceptibility to antibiotics were identified after prolonged exposure to sublethal HEPB concentrations. Transposon mutagenesis and RNA-sequencing analysis identified multiple genetic pathways associated with HEPB exposure, including stress response mechanisms, altered permeability, regulation of intracellular pH, damage and repair of intracellular components, and alteration and repair of lipopolysaccharides. Key pathways included the stringent response, homeostasis of intracellular pH by the kdp operon, protection against electrophiles by KefC, and repair of oxidized proteins by methionine sulfoxide reductase enzymes. In summary, we show that HEPB has potent, targeted efficacy against Burkholderia bacteria without promoting wider stable antimicrobial resistance. The mode of action of HEPB against Burkholderia is multifactorial, but killing by intracellular oxidation is a key mechanism of this promising agent.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Biosciences
Publisher: American Society for Microbiology
ISSN: 0099-2240
Date of First Compliant Deposit: 28 July 2020
Date of Acceptance: 27 July 2020
Last Modified: 12 Feb 2021 23:27
URI: http://orca.cf.ac.uk/id/eprint/133835

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