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Characterization of ceftazidime resistance mechanisms in clinical isolates of Burkholderia pseudomallei from Australia.

Sarovich, Derek S., Price, Erin P., von Schulze, Alex T., Cook, James M., Mayo, Mark J., Watson, Lindsey M., Richardson, Leisha J., Seymour, Meagan L., Tuanyok, Apichai, Engelthaler, David M., Pearson, Talima, Peacock, Sharon J., Currie, Bart J., Keim, Paul and Wagner, David M. (2012). Characterization of ceftazidime resistance mechanisms in clinical isolates of Burkholderia pseudomallei from Australia.. PLoS One,7(2):e30789.

Document type: Journal Article
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IRMA ID kmckayxPUB60
NHMRC Grant No. 383504
605820
Title Characterization of ceftazidime resistance mechanisms in clinical isolates of Burkholderia pseudomallei from Australia.
Author Sarovich, Derek S.
Price, Erin P.
von Schulze, Alex T.
Cook, James M.
Mayo, Mark J.
Watson, Lindsey M.
Richardson, Leisha J.
Seymour, Meagan L.
Tuanyok, Apichai
Engelthaler, David M.
Pearson, Talima
Peacock, Sharon J.
Currie, Bart J.
Keim, Paul
Wagner, David M.
Journal Name PLoS One
Publication Date 2012
Volume Number 7
Issue Number 2
ISSN 1932-6203   (check CDU catalogue open catalogue search in new window)
Scopus ID 2-s2.0-84857387121
Start Page e30789
Total Pages 8
Place of Publication United States
Publisher Public Library of Science
HERDC Category C1 - Journal Article (DIISR)
Abstract Burkholderia pseudomallei is a Gram-negative bacterium that causes the serious human disease, melioidosis. There is no vaccine against melioidosis and it can be fatal if not treated with a specific antibiotic regimen, which typically includes the third-generation cephalosporin, ceftazidime (CAZ). There have been several resistance mechanisms described for B. pseudomallei, of which the best described are amino acid changes that alter substrate specificity in the highly conserved class A β-lactamase, PenA. In the current study, we sequenced penA from isolates sequentially derived from two melioidosis patients with wild-type (1.5 µg/mL) and, subsequently, resistant (16 or ≥256 µg/mL) CAZ phenotypes. We identified two single-nucleotide polymorphisms (SNPs) that directly increased CAZ hydrolysis. One SNP caused an amino acid substitution (C69Y) near the active site of PenA, whereas a second novel SNP was found within the penA promoter region. In both instances, the CAZ resistance phenotype corresponded directly with the SNP genotype. Interestingly, these SNPs appeared after infection and under selection from CAZ chemotherapy. Through heterologous cloning and expression, and subsequent allelic exchange in the native bacterium, we confirmed the role of penA in generating both low-level and high-level CAZ resistance in these clinical isolates. Similar to previous studies, the amino acid substitution altered substrate specificity to other β-lactams, suggesting a potential fitness cost associated with this mutation, a finding that could be exploited to improve therapeutic outcomes in patients harboring CAZ resistant B. pseudomallei. Our study is the first to functionally characterize CAZ resistance in clinical isolates of B. pseudomallei and to provide proven and clinically relevant signatures for monitoring the development of antibiotic resistance in this important pathogen.

DOI http://dx.doi.org/10.1371/journal.pone.0030789   (check subscription with CDU E-Gateway service for CDU Staff and Students  check subscription with CDU E-Gateway in new window)


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