Targeting the Nonmevalonate Pathway in Burkholderia cenocepacia Increases Susceptibility to Certain β-Lactam Antibiotics.

The nonmevalonate pathway is the sole pathway for isoprenoid biosynthesis in and is possibly a novel target for the development of antibacterial chemotherapy. The goals of the present study were to evaluate the essentiality of , the second gene of the nonmevalonate pathway, in and to determine whether interfering with the nonmevalonate pathway increases susceptibility toward antibiotics. To this end, a rhamnose-inducible conditional knockdown mutant of strain K56-2 ( K56-2) was constructed, using a plasmid which enables the delivery of a rhamnose-inducible promoter in the chromosome. Expression of is essential for bacterial growth; the growth defect observed in the mutant could be complemented by expressing under the control of a constitutive promoter, but not by providing 2--methyl-d-erythritol-4-phosphate, the reaction product of DXR (1-deoxy-d-xylulose 5-phosphate reductoisomerase). K56-2 showed markedly increased susceptibility to the β-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 expression of 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 and suggest that combining potent DXR inhibitors with selected β-lactam antibiotics is a useful strategy to combat infections.