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JAC Advance Access originally published online on August 18, 2009
Journal of Antimicrobial Chemotherapy 2009 64(4):735-740; doi:10.1093/jac/dkp299
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© The Author 2009. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

XF-73, a novel antistaphylococcal membrane-active agent with rapid bactericidal activity

Nicola Ooi1, Keith Miller1, Joanne Hobbs1, William Rhys-Williams2, William Love2 and Ian Chopra1,*

1 Antimicrobial Research Centre and Institute of Molecular and Cellular Biology, University of Leeds, Leeds, UK 2 Destiny Pharma Limited, Science Park Square, Falmer, Brighton, UK

Received 18 May 2009; returned 18 June 2009; revised 10 July 2009; accepted 26 July 2009

* Corresponding author. Tel: +44-113-233-5604; Fax: +44-113-233-5638; E-mail: i.chopra{at}leeds.ac.uk

Objectives: XF-73 is a novel porphyrin antibacterial agent previously reported to inhibit a range of Gram-positive bacterial species, including Staphylococcus aureus. Its mode of action is unknown. Using S. aureus as a model organism we sought to examine the basis of its antibacterial activity.

Methods: The effects of XF-73 on the growth and survival of S. aureus SH1000 were investigated by viable count and culture absorbance techniques. Inhibition of macromolecular synthesis and disruption of membrane integrity after exposure to XF-73 were examined by radiolabelling experiments, the BacLight fluorescent dye assay and measurement of K+ and ATP leakage from the cell. The effect of XF-73 on a staphylococcal coupled transcription–translation system was also investigated.

Results: XF-73 was rapidly bactericidal against S. aureus SH1000 and demonstrated more rapid killing kinetics than all other comparator agents when tested at an equivalent multiple (4x) of the MIC. Exposure of S. aureus to XF-73 for 10 min completely inhibited DNA, RNA and protein synthesis. XF-73 had no effect on transcription and translation in vitro. Cells exposed to XF-73 gave a positive response in the BacLight assay, which detects membrane damage. The drug also caused substantial loss of K+ and ATP from the cell, but did not promote bacterial lysis.

Conclusions: XF-73 exhibited rapid membrane-perturbing activity, which is likely to be responsible for inhibition of macromolecular synthesis and the death of staphylococci exposed to the drug.

Keywords: drug action , membrane permeability , membrane integrity , Staphylococcus aureus


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