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

Autor:	Chirakul S; University of Florida, College of Medicine, Emerging Pathogens Institute, Department of Molecular Genetics and Microbiology, Gainesville, FL, 32610, USA., Norris MH; University of Florida, College of Veterinary Medicine, Emerging Pathogens Institute, Department of Infectious Diseases and Immunity, Gainesville, FL, 32610, USA., Pagdepanichkit S; University of Florida, College of Medicine, Emerging Pathogens Institute, Department of Molecular Genetics and Microbiology, Gainesville, FL, 32610, USA.; Chulalongkorn University, Faculty of Veterinary Science, Department of Veterinary Public Health, Research Unit in Microbial Food Safety and Antimicrobial Resistance, Bangkok, 10330, Thailand., Somprasong N; University of Florida, College of Medicine, Emerging Pathogens Institute, Department of Molecular Genetics and Microbiology, Gainesville, FL, 32610, USA., Randall LB; University of Florida, College of Medicine, Emerging Pathogens Institute, Department of Molecular Genetics and Microbiology, Gainesville, FL, 32610, USA.; Cornell University, Boyd Thompson Institute, Ithaca, NY, 14853, USA., Shirley JF; University of Florida, College of Medicine, Emerging Pathogens Institute, Department of Molecular Genetics and Microbiology, Gainesville, FL, 32610, USA., Borlee BR; Colorado State University, College of Veterinary Medicine and Biomedical Sciences, Department of Microbiology, Immunology and Pathology, Fort Collins, CO, 80523, USA., Lomovskaya O; The Medicines Company, San Diego, CA, 92121, USA., Tuanyok A; University of Florida, College of Veterinary Medicine, Emerging Pathogens Institute, Department of Infectious Diseases and Immunity, Gainesville, FL, 32610, USA., Schweizer HP; University of Florida, College of Medicine, Emerging Pathogens Institute, Department of Molecular Genetics and Microbiology, Gainesville, FL, 32610, USA. hschweizer@ufl.edu.
Jazyk:	angličtina
Zdroj:	Scientific reports [Sci Rep] 2018 Jul 13; Vol. 8 (1), pp. 10652. Date of Electronic Publication: 2018 Jul 13.
DOI:	10.1038/s41598-018-28843-7
Abstrakt:	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.
Databáze:	MEDLINE
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