Targeting the Nonmevalonate Pathway inBurkholderia cenocepaciaIncreases Susceptibility to Certain β-Lactam Antibiotics
ABSTRACTThe nonmevalonate pathway is the sole pathway for isoprenoid biosynthesis inBurkholderia cenocepaciaand is possibly a novel target for the development of antibacterial chemotherapy. The goals of the present study were to evaluate the essentiality ofdxr, the second gene of the nonmevalonate pathway, inB. cenocepaciaand to determine whether interfering with the nonmevalonate pathway increases susceptibility toward antibiotics. To this end, a rhamnose-inducible conditionaldxrknockdown mutant ofB. cenocepaciastrain K56-2 (B. cenocepaciaK56-2dxr) was constructed, using a plasmid which enables the delivery of a rhamnose-inducible promoter in the chromosome. Expression ofdxris essential for bacterial growth; the growth defect observed in thedxrmutant could be complemented by expressingdxr in transunder the control of a constitutive promoter, but not by providing 2-C-methyl-d-erythritol-4-phosphate, the reaction product of DXR (1-deoxy-d-xylulose 5-phosphate reductoisomerase).B. cenocepaciaK56-2dxrshowed 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 byin transexpression ofdxr. 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 inB. cenocepaciaand suggest that combining potent DXR inhibitors with selected β-lactam antibiotics is a useful strategy to combatB. cenocepaciainfections.