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Targeting the nonmevalonate pathway in Burkholderia cenocepacia increases susceptibility to certain β-lactam antibiotics

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Abstract
The nonmevalonate pathway is the sole pathway for isoprenoid biosynthesis in Burkholderia cenocepacia and is possibly a novel target for the development of antibacterial chemotherapy. The goals of the present study were to evaluate the essentiality of dxr, the second gene of the nonmevalonate pathway, in B. cenocepacia and to determine whether interfering with the nonmevalonate pathway increases susceptibility toward antibiotics. To this end, a rhamnose-inducible conditional dxr knockdown mutant of B. cenocepacia strain K56-2 (B. cenocepacia K56-2dxr) was constructed, using a plasmid which enables the delivery of a rhamnose-inducible promoter in the chromosome. Expression of dxr is essential for bacterial growth; the growth defect observed in the dxr mutant could be complemented by expressing dxr in trans under the control of a constitutive promoter, but not by providing 2C-methyl-D-erythritol-4-phosphate, the reaction product of DXR (1-deoxy-D-xylulose 5-phosphate reductoisomerase). B. cenocepacia K56-2dxr showed markedly increased susceptibility to the beta-lactam antibiotics aztreonam, ceftazidime, and cefotaxime, while susceptibility to other antibiotics was not (or was much less) affected; this increased susceptibility could also be complemented by in trans expression of dxr. A similarly increased susceptibility was observed when antibiotics were combined with FR900098, a known DXR inhibitor. Our data confirm that the nonmevalonate pathway is essential in B. cenocepacia and suggest that combining potent DXR inhibitors with selected beta-lactam antibiotics is a useful strategy to combat B. cenocepacia infections.
Keywords
SUBSTITUTED FOSMIDOMYCIN ANALOGS, RHAMNOSE-INDUCIBLE PROMOTER, ANTIMICROBIAL RESISTANCE, BIOSYNTHESIS, REDUCTOISOMERASE, AMINOARABINOSE, IDENTIFICATION, MULTIVORANS, PROTEINS, BACTERIA, nonmevalonate pathway, Burkholderia cenocepacia, DXR, Burkholderia, cepacia complex, beta-lactam antibiotics

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Citation

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MLA
Sass, Andrea, Annelien Everaert, Heleen Van Acker, et al. “Targeting the Nonmevalonate Pathway in Burkholderia Cenocepacia Increases Susceptibility to Certain Β-lactam Antibiotics.” ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 62.5 (2018): n. pag. Print.
APA
Sass, A., Everaert, A., Van Acker, H., Van den Driessche, F., & Coenye, T. (2018). Targeting the nonmevalonate pathway in Burkholderia cenocepacia increases susceptibility to certain β-lactam antibiotics. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 62(5).
Chicago author-date
Sass, Andrea, Annelien Everaert, Heleen Van Acker, Freija Van den Driessche, and Tom Coenye. 2018. “Targeting the Nonmevalonate Pathway in Burkholderia Cenocepacia Increases Susceptibility to Certain Β-lactam Antibiotics.” Antimicrobial Agents and Chemotherapy 62 (5).
Chicago author-date (all authors)
Sass, Andrea, Annelien Everaert, Heleen Van Acker, Freija Van den Driessche, and Tom Coenye. 2018. “Targeting the Nonmevalonate Pathway in Burkholderia Cenocepacia Increases Susceptibility to Certain Β-lactam Antibiotics.” Antimicrobial Agents and Chemotherapy 62 (5).
Vancouver
1.
Sass A, Everaert A, Van Acker H, Van den Driessche F, Coenye T. Targeting the nonmevalonate pathway in Burkholderia cenocepacia increases susceptibility to certain β-lactam antibiotics. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY. 2018;62(5).
IEEE
[1]
A. Sass, A. Everaert, H. Van Acker, F. Van den Driessche, and T. Coenye, “Targeting the nonmevalonate pathway in Burkholderia cenocepacia increases susceptibility to certain β-lactam antibiotics,” ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, vol. 62, no. 5, 2018.
@article{8565436,
  abstract     = {The nonmevalonate pathway is the sole pathway for isoprenoid biosynthesis in Burkholderia cenocepacia and is possibly a novel target for the development of antibacterial chemotherapy. The goals of the present study were to evaluate the essentiality of dxr, the second gene of the nonmevalonate pathway, in B. cenocepacia and to determine whether interfering with the nonmevalonate pathway increases susceptibility toward antibiotics. To this end, a rhamnose-inducible conditional dxr knockdown mutant of B. cenocepacia strain K56-2 (B. cenocepacia K56-2dxr) was constructed, using a plasmid which enables the delivery of a rhamnose-inducible promoter in the chromosome. Expression of dxr is essential for bacterial growth; the growth defect observed in the dxr mutant could be complemented by expressing dxr in trans under the control of a constitutive promoter, but not by providing 2C-methyl-D-erythritol-4-phosphate, the reaction product of DXR (1-deoxy-D-xylulose 5-phosphate reductoisomerase). B. cenocepacia K56-2dxr showed markedly increased susceptibility to the beta-lactam antibiotics aztreonam, ceftazidime, and cefotaxime, while susceptibility to other antibiotics was not (or was much less) affected; this increased susceptibility could also be complemented by in trans expression of dxr. A similarly increased susceptibility was observed when antibiotics were combined with FR900098, a known DXR inhibitor. Our data confirm that the nonmevalonate pathway is essential in B. cenocepacia and suggest that combining potent DXR inhibitors with selected beta-lactam antibiotics is a useful strategy to combat B. cenocepacia infections.},
  articleno    = {e02607-17},
  author       = {Sass, Andrea and Everaert, Annelien and Van Acker, Heleen and Van den Driessche, Freija and Coenye, Tom},
  issn         = {0066-4804},
  journal      = {ANTIMICROBIAL AGENTS AND CHEMOTHERAPY},
  keywords     = {SUBSTITUTED FOSMIDOMYCIN ANALOGS,RHAMNOSE-INDUCIBLE PROMOTER,ANTIMICROBIAL RESISTANCE,BIOSYNTHESIS,REDUCTOISOMERASE,AMINOARABINOSE,IDENTIFICATION,MULTIVORANS,PROTEINS,BACTERIA,nonmevalonate pathway,Burkholderia cenocepacia,DXR,Burkholderia,cepacia complex,beta-lactam antibiotics},
  language     = {eng},
  number       = {5},
  pages        = {9},
  title        = {Targeting the nonmevalonate pathway in Burkholderia cenocepacia increases susceptibility to certain β-lactam antibiotics},
  url          = {http://dx.doi.org/10.1128/AAC.02607-17},
  volume       = {62},
  year         = {2018},
}

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