Cargando…

Transcriptional and post-transcriptional regulation of PenA β-lactamase in acquired Burkholderia pseudomallei β-lactam resistance

Therapy of Burkholderia pseudomallei acute infections is largely limited to a few β-lactam antibiotics such as ceftazidime or meropenem. Although relatively rare, resistance emergence during therapy leads to treatment failures with high mortality rates. In the absence of acquired external resistance...

Descripción completa

Detalles Bibliográficos
Autores principales: Chirakul, Sunisa, Norris, Michael H., Pagdepanichkit, Sirawit, Somprasong, Nawarat, Randall, Linnell B., Shirley, James F., Borlee, Bradley R., Lomovskaya, Olga, Tuanyok, Apichai, Schweizer, Herbert P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6045580/
https://www.ncbi.nlm.nih.gov/pubmed/30006637
http://dx.doi.org/10.1038/s41598-018-28843-7
_version_ 1783339680453885952
author Chirakul, Sunisa
Norris, Michael H.
Pagdepanichkit, Sirawit
Somprasong, Nawarat
Randall, Linnell B.
Shirley, James F.
Borlee, Bradley R.
Lomovskaya, Olga
Tuanyok, Apichai
Schweizer, Herbert P.
author_facet Chirakul, Sunisa
Norris, Michael H.
Pagdepanichkit, Sirawit
Somprasong, Nawarat
Randall, Linnell B.
Shirley, James F.
Borlee, Bradley R.
Lomovskaya, Olga
Tuanyok, Apichai
Schweizer, Herbert P.
author_sort Chirakul, Sunisa
collection PubMed
description Therapy of Burkholderia pseudomallei acute infections is largely limited to a few β-lactam antibiotics such as ceftazidime or meropenem. Although relatively rare, resistance emergence during therapy leads to treatment failures with high mortality rates. In the absence of acquired external resistance determinants in B. pseudomallei emergence of β-lactam resistance is invariably caused by mutational modification of genomically encoded factors. These include the deletion of the ceftazidime target penicillin-binding protein 3 or amino acid changes in the Class A PenA β-lactamase that expand its substrate spectrum, as well as penA gene duplication and amplification or its overexpression via transcriptional up-regulation. Evidence is presented that penA is co-transcribed with the upstream nlpD1 gene, that the transcriptional terminator for nlpD1 serves as a penA attenuator and that generation of a new promoter immediately upstream of the terminator/attenuator by a conserved G to A transition leads to anti-termination and thus constitutive PenA expression and extended β-lactam resistance. Further evidence obtained with the extensively β-lactam resistant clinical isolate Bp1651 shows that in addition to PenA overexpression and structural mutations other adaptive mechanisms contribute to intrinsic and acquired B. pseudomallei β-lactam resistance.
format Online
Article
Text
id pubmed-6045580
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-60455802018-07-16 Transcriptional and post-transcriptional regulation of PenA β-lactamase in acquired Burkholderia pseudomallei β-lactam resistance Chirakul, Sunisa Norris, Michael H. Pagdepanichkit, Sirawit Somprasong, Nawarat Randall, Linnell B. Shirley, James F. Borlee, Bradley R. Lomovskaya, Olga Tuanyok, Apichai Schweizer, Herbert P. Sci Rep Article Therapy of Burkholderia pseudomallei acute infections is largely limited to a few β-lactam antibiotics such as ceftazidime or meropenem. Although relatively rare, resistance emergence during therapy leads to treatment failures with high mortality rates. In the absence of acquired external resistance determinants in B. pseudomallei emergence of β-lactam resistance is invariably caused by mutational modification of genomically encoded factors. These include the deletion of the ceftazidime target penicillin-binding protein 3 or amino acid changes in the Class A PenA β-lactamase that expand its substrate spectrum, as well as penA gene duplication and amplification or its overexpression via transcriptional up-regulation. Evidence is presented that penA is co-transcribed with the upstream nlpD1 gene, that the transcriptional terminator for nlpD1 serves as a penA attenuator and that generation of a new promoter immediately upstream of the terminator/attenuator by a conserved G to A transition leads to anti-termination and thus constitutive PenA expression and extended β-lactam resistance. Further evidence obtained with the extensively β-lactam resistant clinical isolate Bp1651 shows that in addition to PenA overexpression and structural mutations other adaptive mechanisms contribute to intrinsic and acquired B. pseudomallei β-lactam resistance. Nature Publishing Group UK 2018-07-13 /pmc/articles/PMC6045580/ /pubmed/30006637 http://dx.doi.org/10.1038/s41598-018-28843-7 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Chirakul, Sunisa
Norris, Michael H.
Pagdepanichkit, Sirawit
Somprasong, Nawarat
Randall, Linnell B.
Shirley, James F.
Borlee, Bradley R.
Lomovskaya, Olga
Tuanyok, Apichai
Schweizer, Herbert P.
Transcriptional and post-transcriptional regulation of PenA β-lactamase in acquired Burkholderia pseudomallei β-lactam resistance
title Transcriptional and post-transcriptional regulation of PenA β-lactamase in acquired Burkholderia pseudomallei β-lactam resistance
title_full Transcriptional and post-transcriptional regulation of PenA β-lactamase in acquired Burkholderia pseudomallei β-lactam resistance
title_fullStr Transcriptional and post-transcriptional regulation of PenA β-lactamase in acquired Burkholderia pseudomallei β-lactam resistance
title_full_unstemmed Transcriptional and post-transcriptional regulation of PenA β-lactamase in acquired Burkholderia pseudomallei β-lactam resistance
title_short Transcriptional and post-transcriptional regulation of PenA β-lactamase in acquired Burkholderia pseudomallei β-lactam resistance
title_sort transcriptional and post-transcriptional regulation of pena β-lactamase in acquired burkholderia pseudomallei β-lactam resistance
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6045580/
https://www.ncbi.nlm.nih.gov/pubmed/30006637
http://dx.doi.org/10.1038/s41598-018-28843-7
work_keys_str_mv AT chirakulsunisa transcriptionalandposttranscriptionalregulationofpenablactamaseinacquiredburkholderiapseudomalleiblactamresistance
AT norrismichaelh transcriptionalandposttranscriptionalregulationofpenablactamaseinacquiredburkholderiapseudomalleiblactamresistance
AT pagdepanichkitsirawit transcriptionalandposttranscriptionalregulationofpenablactamaseinacquiredburkholderiapseudomalleiblactamresistance
AT somprasongnawarat transcriptionalandposttranscriptionalregulationofpenablactamaseinacquiredburkholderiapseudomalleiblactamresistance
AT randalllinnellb transcriptionalandposttranscriptionalregulationofpenablactamaseinacquiredburkholderiapseudomalleiblactamresistance
AT shirleyjamesf transcriptionalandposttranscriptionalregulationofpenablactamaseinacquiredburkholderiapseudomalleiblactamresistance
AT borleebradleyr transcriptionalandposttranscriptionalregulationofpenablactamaseinacquiredburkholderiapseudomalleiblactamresistance
AT lomovskayaolga transcriptionalandposttranscriptionalregulationofpenablactamaseinacquiredburkholderiapseudomalleiblactamresistance
AT tuanyokapichai transcriptionalandposttranscriptionalregulationofpenablactamaseinacquiredburkholderiapseudomalleiblactamresistance
AT schweizerherbertp transcriptionalandposttranscriptionalregulationofpenablactamaseinacquiredburkholderiapseudomalleiblactamresistance