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Fosmidomycin Decreases Membrane Hopanoids and Potentiates the Effects of Colistin on Burkholderia multivorans Clinical Isolates

Malott, Rebecca J. and Wu, Chia-Hung and Lee, Tracy D. and Hird, Trevor J. and Dalleska, Nathan F. and Zlosnik, James E. A. and Newman, Dianne K. and Speert, David P. (2014) Fosmidomycin Decreases Membrane Hopanoids and Potentiates the Effects of Colistin on Burkholderia multivorans Clinical Isolates. Antimicrobial Agents and Chemotherapy, 58 (9). pp. 5211-5219. ISSN 0066-4804. PMCID PMC4135860. http://resolver.caltech.edu/CaltechAUTHORS:20141007-095444557

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Abstract

Burkholderia cepacia complex (Bcc) pulmonary infections in people living with cystic fibrosis (CF) are difficult to treat because of the extreme intrinsic resistance of most isolates to a broad range of antimicrobials. Fosmidomycin is an antibacterial and antiparasitic agent that disrupts the isoprenoid biosynthesis pathway, a precursor to hopanoid biosynthesis. Hopanoids are involved in membrane stability and contribute to polymyxin resistance in Bcc bacteria. Checkerboard MIC assays determined that although isolates of the Bcc species B. multivorans were highly resistant to treatment with fosmidomycin or colistin (polymyxin E), antimicrobial synergy was observed in certain isolates when the antimicrobials were used in combination. Treatment with fosmidomycin decreased the MIC of colistin for isolates as much as 64-fold to as low as 8 μg/ml, a concentration achievable with colistin inhalation therapy. A liquid chromatography-tandem mass spectrometry technique was developed for the accurate quantitative determination of underivatized hopanoids in total lipid extracts, and bacteriohopanetetrol cyclitol ether (BHT-CE) was found to be the dominant hopanoid made by B. multivorans. The amount of BHT-CE made was significantly reduced upon fosmidomycin treatment of the bacteria. Uptake assays with 1-N-phenylnaphthylamine were used to determine that dual treatment with fosmidomycin and colistin increases membrane permeability, while binding assays with boron-dipyrromethene-conjugated polymyxin B illustrated that the addition of fosmidomycin had no impact on polymyxin binding. This work indicates that pharmacological suppression of membrane hopanoids with fosmidomycin treatment can increase the susceptibility of certain clinical B. multivorans isolates to colistin, an agent currently in use to treat pulmonary infections in CF patients.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1128/AAC.02705-14DOIArticle
http://aac.asm.org/content/58/9/5211PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4135860/PubMed CentralArticle
ORCID:
AuthorORCID
Dalleska, Nathan F.0000-0002-2059-1587
Newman, Dianne K.0000-0003-1647-1918
Additional Information:© 2014 American Society for Microbiology. Received 11 March 2014; Returned for modification 20 April 2014; Accepted 14 June 2014; Published ahead of print 23 June 2014. We thank S. D. Gray-Owen of the University of Toronto for generously providing laboratory space and reagents. R.J.M. received fellowship funding from Cystic Fibrosis Canada (CFC) and the Canadian Institutes of Health Research (CIHR). J.E.A.Z. received fellowship funding from CFC. This work was supported by operating funds from CFC. The UPLC-TOFMSequipment in the California Institute of Technology’s Environmental Analysis Center was used in the work described here. This work was also supported by grants from NASA (NNX12AD93G), the National Science Foundation (1224158), and the Howard Hughes Medical Institute (HHMI) to D.K.N. D.K.N. is anHHMI Investigator.
Funders:
Funding AgencyGrant Number
Cystic Fibrosis CanadaUNSPECIFIED
Canadian Institutes of Health Research (CIHR)UNSPECIFIED
NASANNX12AD93G
NSFCHE-1224158
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
PubMed Central ID:PMC4135860
Record Number:CaltechAUTHORS:20141007-095444557
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20141007-095444557
Official Citation:Malott, R. J., Wu, C.-H., Lee, T. D., Hird, T. J., Dalleska, N. F., Zlosnik, J. E. A., . . . Speert, D. P. (2014). Fosmidomycin Decreases Membrane Hopanoids and Potentiates the Effects of Colistin on Burkholderia multivorans Clinical Isolates. Antimicrobial Agents and Chemotherapy, 58(9), 5211-5219. doi: 10.1128/aac.02705-14
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:50224
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:07 Oct 2014 19:52
Last Modified:24 Oct 2017 16:22

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