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

Sunisa Chirakul, Michael H. Norris, Sirawit Pagdepanichkit, Nawarat Somprasong, Linnell B. Randall, James F. Shirley, Bradley R. Borlee, Olga Lomovskaya, Apichai Tuanyok, Herbert P. Schweizer

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number10652
JournalScientific Reports
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018
Externally publishedYes

ASJC Scopus subject areas

  • General

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