Award details

Antibacterial activity and mode of action of lipophilic antioxidants

Reference	BB/G017158/1
Principal Investigator / Supervisor	Professor Alex O'Neill
Co-Investigators / Co-Supervisors
Institution	University of Leeds
Department	Inst of Molecular & Cellular Biology
Funding type	Skills
Value (£)	74,410
Status	Completed
Type	Training Grants
Start date	01/10/2009
End date	30/09/2013
Duration	48 months

Abstract

unavailable

Summary

Antibacterial activity and mode of action of lipophilic antioxidants Syntopix has patent applications to protect the use of two lipophilic antioxidants (LAs), tert-butyl hydroquinone (TBHQ) and AO 2246, as novel anti-acne agents. The patent on TBHQ is granted in the UK, as are further patents covering synergies between TBHQ and several metal salts as antimicrobial agents. Both LAs demonstrate good activity against a range of Gram-positive bacteria, including Staphylococcus aureus and Propionibacterium acnes, with minimum inhibitory concentrations of <10 mg/L. The antibacterial activity is not the result of a generalised biocidal activity, since neither compound is active against Gram-negative bacteria or yeast. These compounds have excellent potential for use in the field of dermatology, and specifically in the topical treatment of acne, and may also prove useful in other areas of healthcare where topical or local delivery is appropriate. This study aims to further characterize the antibacterial activity and mode(s) of action of these LAs, thereby providing a basis for guiding future research, development and eventual use of these agents. The O'Neill laboratory has extensive experience in characterizing the antibacterial effects of both organic and inorganic antibacterial agents (2) primarily using the important bacterial pathogen, Staphylococcus aureus, as a model organism. This established expertise will be brought to bear on three major areas of joint interest to Syntopix and the O'Neill laboratory; Mode of action: The antibacterial mechanism of action of LAs is unclear, but is thought to involve the production of free radicals that damage the bacterial membrane. To investigate the role of free radical production, the quantity and types of radical produced in aqueous solutions/growth media will be determined. To relate radical formation to antibacterial activity, susceptibility testing will be conducted in the presence of terminal antioxidants (quenchers), toestablish whether the antibacterial effect mediated by LAs is lost. Damage occurring at the level of the bacterial membrane will be characterized in detail by electron microscopy, and through use of a panel of membrane damage assays that are already well-established in the O'Neill lab (1, 3). To further investigate the cellular target(s) of LAs in bacteria, staphylococcal mutants exhibiting reduced susceptibility to these agents will be generated, and the genetic changes in these mutants mapped by Comparative Genome Sequencing (CGS). Activity and synergy: Combining LAs with metal salts or benzoyl peroxide results in synergistic effects upon antibacterial activity. Furthermore, combining the LAs of interest with other LAs, or each other, may also potentiate antibacterial activity. The antibacterial activity of these combinations will be examined in detail. In conjunction with information arising from mode of action studies, the molecular basis for these synergistic interactions will be interrogated. Toxicity: Although it has been established that the LAs of interest show a degree of selective toxicity against Gram-positive bacteria compared with eukaryotic cells, further characterization of this phenomenon is required. The activity of these LAs against types of mammalian cells that the compound might interact with upon topical delivery (e.g. keratinocytes, fibroblasts and oral mucosa) will be evaluated. Where appropriate, further experiments will be performed to determine the basis for the selective toxicity of LAs. 1. Hobbs, J. K., K. Miller, A. J. O'Neill, and I. Chopra. 2008. Journal of Antimicrobial Chemotherapy. doi:10.1093/jac/dkn321 2. O'Neill, A. J., and I. Chopra. 2004. Expert Opinion on Investigational Drugs 13:1045-63. 3. O'Neill, A. J., K. Miller, B. Oliva, and I. Chopra. 2004. Journal of Antimicrobial Chemotherapy 54:1127-1129.

Committee	Not funded via Committee
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	Training Grant - Industrial Case

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