In view of the increasing global challenge of bacterial resistance, there exists an urgent need for the rationale development of antibacterial compounds with either novel or multiple mechanisms of action. Two chalcone-derivatives, F1 and F23, demonstrated MICs within the range of 16 to >512 μg/ml against two plant pathogens (P. caratovoram and C. michiganensis subsp. michiganensis) as well as important clinical bacterial species. Both compounds displayed an MIC of 32 μg/ml against quinolone-resistant S. aureus. Whilst possessing weak activities individually, each semi-synthetic agent displayed notable synergistic action with polymyxin B against S. aureus, C. violaceum, E. coli and Ps. aeruginosa, thereby recording FICs within the range of <0.093 to 2 that indicated the existence of synergism in some instance. These chalcone compounds applied with polymyxin B displayed a notable FICindex of <0.093 against the Neisseriaceae C. violaceum, and a potential noteworthy capacity to extend the spectrum of activity of the latter antibiotic to include Gram-positive S. aureus species. F1 inhibited staphylococcal replication in broth and the combination of either of both chalcone-derivatives with polymyxin B instituted a metabolic blockage in S. aureus and other bacterial species as determined through a modified MTT reduction assay. The combined agents inflicted major disruptions to the S. aureus cytoplasmic membrane bilayer as evidenced by the release of intracellular potassium as well as the influx of Sytox Green fluorescent stain. Notable levels of cell membrane potential dissipation, leakage of intracellular potassium ions and blockage of reducing enzymes activities occurred within the first 30 minutes, well in advance of significant loss in cell viability that was recorded usually after 4 – 8 hours, suggesting these activities were prerequisites to cell death. In erythrocyte lysis assay, the synergistic combinations of 128 μg/ml of either of both chalcone derivatives with 128 μg/ml polymyxin B displayed the lowest degree of haemolysis, followed by that occurring with 32 μg/ml of the chalcone-derivatives combined with 256 μg/ml of the polypeptide antibiotic. In conclusion, further structure activity modifications aimed at improving the aqueous solubility of these chalcone-derivatives as well as the antibacterial activity recorded for certain combination concentrations of polymyxin B with either of these semi-synthetic agents may be required before considerations are made for the possibility for potential external formulations. Such preparations may include antiseptic creams, lotions, ointments, as well as aerosols that can be applied with nebulizers in targeted delivery for such cases like cystic fibrosis.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:577162 |
| Date | January 2013 |
| Creators | Medu, Erere Ohwofasa |
| Contributors | Lamb, Andrew; Matthews, Kerr H.; Di Salvo, Alberto |
| Publisher | Robert Gordon University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/10059/832 |
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