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dc.contributor.authorDerek S. Sarovichen_US
dc.contributor.authorErin P. Priceen_US
dc.contributor.authorAlex T. von Schulzeen_US
dc.contributor.authorJames M. Cooken_US
dc.contributor.authorMark Mayoen_US
dc.contributor.authorLindsey M. Watsonen_US
dc.contributor.authorLeisha Richardsonen_US
dc.contributor.authorMeagan L. Seymouren_US
dc.contributor.authorApichai Tuanyoken_US
dc.contributor.authorDavid M. Engelthaleren_US
dc.contributor.authorTalima Pearsonen_US
dc.contributor.authorSharon J. Peacocken_US
dc.contributor.authorBart J. Currieen_US
dc.contributor.authorPaul Keimen_US
dc.contributor.authorDavid M. Wagneren_US
dc.contributor.otherNorthern Arizona Universityen_US
dc.contributor.otherMenzies School of Health Researchen_US
dc.contributor.otherTranslational Genomics Research Instituteen_US
dc.contributor.otherMahidol Universityen_US
dc.contributor.otherUniversity of Cambridgeen_US
dc.date.accessioned2018-06-11T04:31:27Z-
dc.date.available2018-06-11T04:31:27Z-
dc.date.issued2012-02-21en_US
dc.identifier.citationPLoS ONE. Vol.7, No.2 (2012)en_US
dc.identifier.issn19326203en_US
dc.identifier.other2-s2.0-84857387121en_US
dc.identifier.urihttps://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84857387121&origin=inwarden_US
dc.identifier.urihttp://repository.li.mahidol.ac.th/dspace/handle/123456789/13497-
dc.description.abstractBurkholderia 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. © 2012 Sarovich et al.en_US
dc.rightsMahidol Universityen_US
dc.source.urihttps://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84857387121&origin=inwarden_US
dc.subjectAgricultural and Biological Sciencesen_US
dc.subjectBiochemistry, Genetics and Molecular Biologyen_US
dc.subjectMedicineen_US
dc.titleCharacterization of ceftazidime resistance mechanisms in clinical isolates of burkholderia pseudomallei from Australiaen_US
dc.typeArticleen_US
dc.rights.holderSCOPUSen_US
dc.identifier.doi10.1371/journal.pone.0030789en_US
Appears in Collections:Scopus 2011-2015

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