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

Slade A Loutet; Omar M El-Halfawy; Agatha N Jassem; José María Sánchez López; Antonio Fernández Medarde; David P Speert; Julian E Davies; Miguel A Valvano

doi:10.1016/j.ijantimicag.2015.05.010

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

Int J Antimicrob Agents. 2015 Oct;46(4):376-80. doi: 10.1016/j.ijantimicag.2015.05.010. Epub 2015 Jun 22.

Authors

Slade A Loutet¹, Omar M El-Halfawy², Agatha N Jassem³, José María Sánchez López⁴, Antonio Fernández Medarde⁴, David P Speert⁵, Julian E Davies⁶, Miguel A Valvano⁷

Affiliations

¹ 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.
² 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.
³ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
⁴ Biomar Microbial Technologies, León, Spain.
⁵ Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada; Department of Pathology, University of British Columbia, Vancouver, BC, Canada.
⁶ Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada.
⁷ 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.

PMID: 26187366
DOI: 10.1016/j.ijantimicag.2015.05.010

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.

Keywords: Aminocoumarins; Antimicrobial adjuvants; Clorobiocin; Cystic fibrosis; Novobiocin; Polymyxins.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents / pharmacology*
Biological Products / isolation & purification
Biological Products / pharmacology*
Burkholderia cepacia complex / drug effects*
Drug Synergism*
Humans
Polymyxin B / pharmacology*

Substances

Anti-Bacterial Agents
Biological Products
Polymyxin B

Grants and funding

Canadian Institutes of Health Research/Canada