Please use this identifier to cite or link to this item: http://docs.prosentient.com.au/prosentientjspui/handle/1/10712
Title: Loss of Methyltransferase Function and Increased Efflux Activity Leads to Doxycycline Resistance in Burkholderia pseudomallei.
Authors: Webb, Jessica R
Price, Erin P
Currie, Bart J
Sarovich, Derek S
Affiliation: Global and Tropical Health Division, Menzies School of Health Research, Darwin, Northern Territory, Australia..
Global and Tropical Health Division, Menzies School of Health Research, Darwin, Northern Territory, Australia.. Centre for Animal Health Innovation, Faculty of Science, Health, Education and Engineering, University of the Sunshine Coast, Sippy Downs, Queensland, Australia..
Global and Tropical Health Division, Menzies School of Health Research, Darwin, Northern Territory, Australia.. Department of Infectious Diseases and Northern Territory Medical Program, Royal Darwin Hospital, Darwin, Northern Territory, Australia..
Global and Tropical Health Division, Menzies School of Health Research, Darwin, Northern Territory, Australia derek.sarovich@menzies.edu.au.. Centre for Animal Health Innovation, Faculty of Science, Health, Education and Engineering, University of the Sunshine Coast, Sippy Downs, Queensland, Australia..
Issue Date: 2017
Citation: Antimicrobial agents and chemotherapy 2017; 61(6)
Abstract: The soil-dwelling bacterium Burkholderia pseudomallei is the causative agent of the potentially fatal disease melioidosis. The lack of a vaccine toward B. pseudomallei means that melioidosis treatment relies on prolonged antibiotic therapy, which can last up to 6 months in duration or longer. Due to intrinsic resistance, few antibiotics are effective against B. pseudomallei The lengthy treatment regimen required increases the likelihood of resistance development, with subsequent potentially fatal relapse. Doxycycline (DOX) has historically played an important role in the eradication phase of melioidosis treatment. Both primary and acquired DOX resistances have been documented in B. pseudomallei; however, the molecular mechanisms underpinning DOX resistance have remained elusive. Here, we identify and functionally characterize the molecular mechanisms conferring acquired DOX resistance in an isogenic B. pseudomallei pair. Two synergistic mechanisms were identified. The first mutation occurred in a putative S-adenosyl-l-methionine-dependent methyltransferase (encoded by BPSL3085), which we propose leads to altered ribosomal methylation, thereby decreasing DOX binding efficiency. The second mutation altered the function of the efflux pump repressor gene, amrR, resulting in increased expression of the resistance-nodulation-division efflux pump, AmrAB-OprA. Our findings highlight the diverse mechanisms by which B. pseudomallei can become resistant to antibiotics used in melioidosis therapy and the need for resistance monitoring during treatment regimens, especially in patients with prolonged or recrudesced positive cultures for B. pseudomallei.
URI: http://docs.prosentient.com.au/prosentientjspui/handle/1/10712
DOI: 10.1128/AAC.00268-17
ORCID: 0000-0002-1079-4882
0000-0002-6944-3980
Type: Journal Article
Research Support, Non-U.S. Gov't
Subjects: AmrAB-OprA
BPSL3085
Burkholderia pseudomallei
SAM-dependent methyltransferase
amrR
antibiotic resistance
doxycycline
Anti-Bacterial Agents
Burkholderia pseudomallei
Doxycycline
Methyltransferases
Microbial Sensitivity Tests
Mutation
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