An “unlikely” pair: The antimicrobial synergy of polymyxin B in combination with the cystic fibrosis transmembrane conductance regulator drugs KALYDECO and ORKAMBI

Schneider, Elena K., Azad, Mohammad A. K., Han, Mei-Ling, Zhou, Qi (Tony), Wang, Jiping, Huang, Johnny X., Cooper, Matthew A., Doi, Yohei, Baker, Mark A., Bergen, Phillip J., Muller, Mark T., Li, Jian and Velkov, Tony (2016) An “unlikely” pair: The antimicrobial synergy of polymyxin B in combination with the cystic fibrosis transmembrane conductance regulator drugs KALYDECO and ORKAMBI. ACS Infectious Diseases, 2 7: 478-488. doi:10.1021/acsinfecdis.6b00035


Author Schneider, Elena K.
Azad, Mohammad A. K.
Han, Mei-Ling
Zhou, Qi (Tony)
Wang, Jiping
Huang, Johnny X.
Cooper, Matthew A.
Doi, Yohei
Baker, Mark A.
Bergen, Phillip J.
Muller, Mark T.
Li, Jian
Velkov, Tony
Title An “unlikely” pair: The antimicrobial synergy of polymyxin B in combination with the cystic fibrosis transmembrane conductance regulator drugs KALYDECO and ORKAMBI
Journal name ACS Infectious Diseases   Check publisher's open access policy
ISSN 2373-8227
Publication date 2016-05-03
Year available 2016
Sub-type Article (original research)
DOI 10.1021/acsinfecdis.6b00035
Open Access Status Not Open Access
Volume 2
Issue 7
Start page 478
End page 488
Total pages 11
Place of publication Washington DC, United States
Publisher American Chemical Society
Collection year 2017
Language eng
Formatted abstract
Novel combination therapies are desperately needed for combating lung infections caused by bacterial “superbugs”. This study aimed to investigate the synergistic antibacterial activity of polymyxin B in combination with the cystic fibrosis (CF) drugs KALYDECO (ivacaftor) and ORKAMBI (ivacaftor + lumacaftor) against Gram-negative pathogens that commonly colonize the CF lung, in particular, the problematic Pseudomonas aeruginosa. The in vitro synergistic activity of polymyxin B combined with ivacaftor or lumacaftor was assessed using checkerboard and static time-kill assays against a panel of polymyxin-susceptible and polymyxin-resistant P. aeruginosa isolates from the lungs of CF patients. Polymyxin B, ivacaftor, and lumacaftor were ineffective when used individually against polymyxin-resistant (MIC ≥ 4 mg/L) isolates. However, when used together, the combination of clinically relevant concentrations of polymyxin B (2 mg/L) combined with ivacaftor (8 mg/L) or ivacaftor (8 mg/L) + lumacaftor (8 mg/L) displayed synergistic killing activity against polymyxin-resistant P. aeruginosa isolates as demonstrated by a 100-fold decrease in the bacterial count (CFU/mL) even after 24 h. The combinations also displayed excellent antibacterial activity against P. aeruginosa under CF relevant conditions in a sputum medium assay. The combination of lumacaftor (alone) with polymyxin B showed additivity against P. aeruginosa. The potential antimicrobial mode of action of the combinations against P. aeruginosa was investigated using different methods. Treatment with the combinations induced cytosolic GFP release from P. aeruginosa cells and showed permeabilizing activity in the nitrocefin assay, indicating damage to both the outer and inner Gram-negative cell membranes. Moreover, scanning and transmission electron micrographs revealed that the combinations produce outer membrane damage to P. aeruginosa cells that is distinct from the effect of each compound per se. Ivacaftor was also shown to be a weak inhibitor of the bacterial DNA gyrase and topoisomerase IV with no effect on either human type I or type IIα topoisomerases. Lumacaftor displayed the ability to increase the cellular production of damaging reactive oxygen species. In summary, the combination of polymyxin B with KALYDECO or ORKAMBI exhibited synergistic activity against highly polymyxin-resistant P. aeruginosa CF isolates and can be potentially useful for otherwise untreatable CF lung infections.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
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Created: Thu, 26 May 2016, 15:07:30 EST by Susan Allen on behalf of Institute for Molecular Bioscience