title: Identification of synergists that potentiate the action of polymyxin B against Burkholderia cenocepacia.
abstract: 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 synergise with polymyxin B (PMB) to inhibit the growth of B. cenocepacia. At 1 μg/mL, five compounds synergised with PMB and inhibited the growth of B. cenocepacia by ≥70% compared with growth in PMB alone. Follow-up testing revealed that one compound from the screen, the aminocoumarin antibiotic novobiocin, synergised with PMB 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 that these bacteria are even more susceptible to an alternative aminocoumarin, clorobiocin, which also had an additive effect with PMB against B. cenocepacia. These studies support using aminocoumarin antibiotics to treat BCC infections and show that synergisers can be found to increase the efficacy of antimicrobial peptides and polymyxins against BCC bacteria.
authors.affiliation: Centre for Human Immunology, Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada; Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Slade A
authors.initials: SA
authors.lastname: Loutet
authors.affiliation: Centre for Human Immunology, Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada; Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
authors.forename: Omar M
authors.initials: OM
authors.lastname: El-Halfawy
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Agatha N
authors.initials: AN
authors.lastname: Jassem
authors.affiliation: Biomar Microbial Technologies, León, Spain.
authors.forename: José María Sánchez
authors.initials: JM
authors.lastname: López
authors.affiliation: Biomar Microbial Technologies, León, Spain.
authors.forename: Antonio Fernández
authors.initials: AF
authors.lastname: Medarde
authors.affiliation: Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada; Department of Pathology, University of British Columbia, Vancouver, BC, Canada.
authors.forename: David P
authors.initials: DP
authors.lastname: Speert
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Julian E
authors.initials: JE
authors.lastname: Davies
authors.affiliation: Centre for Human Immunology, Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada; Centre for Infection and Immunity, Queen's University Belfast, Belfast, UK. Electronic address: m.valvano@qub.ac.uk.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Valvano
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001688:Biological Products / Q000302:isolation & purification / Q000494:pharmacology*; D042602:Burkholderia cepacia complex / Q000187:drug effects*; D004357:Drug Synergism; D006801:Humans; D011112:Polymyxin B / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D001688:Biological Products; D011112:Polymyxin B
keywords: Aminocoumarins; Antimicrobial adjuvants; Clorobiocin; Cystic fibrosis; Novobiocin; Polymyxins