Identification of synergists that potentiate the action of polymyxin B against Burkholderia cenocepacia

Burkholderia cenocepacia and other members of the Burkholderia cepacia complex (Bcc) are highly multidrug-resistant bacteria that cause severe pulmonary infections in patients with cystic fibrosis. A screen of 2686 compounds derived from marine organisms identified molecules that could synergize with polymyxin B to inhibit growth of B. cenocepacia. At 1 μg/ml, five compounds synergized with polymyxin B and inhibited the growth of B. cenocepacia by more than 70% compared to growth in polymyxin B alone. Follow-up testing revealed that one compound from the screen, the aminocoumarin antibiotic novobiocin, synergized with polymyxin B and colistin against tobramycin-resistant clinical isolates of B. cenocepacia and Burkholderia multivorans. In parallel, we show that novobiocin sensitivity is common among Bcc species and these bacteria are even more susceptible to an alternative aminocoumarin, clorobiocin, which also had an additive effect with polymyxin B against B. cenocepacia. These studies support using aminocoumarin antibiotics to treat Bcc infections and show that synergizers can be found to increase the efficacy of antimicrobial peptides and polymyxins against Bcc bacteria.