Doctor of Philosophy
School of Chemistry - Faculty of Science
Ambrus, Joseph I, Development of potential dual-action antibacterial agents, PhD thesis, School of Chemistry, University of Wollongong, 2008. http://ro.uow.edu.au/theses/67
With the ever-present threat of bacteria becoming resistant to all known antibacterial drugs comes a pressing need to develop new antibacterial agents which circumvent this resistance. One of the major mechanisms of resistance that bacteria employ to compromise the activity of antibacterials is through efflux pumps. These pumps, such as the NorA pump in Staphylococcus aureus, have the ability to extrude a wide range of structurally dissimilar antibiotics, hence conferring multidrug resistance to the bacteria. To date, there have been no therapeutically useful inhibitors of efflux pumps developed and thus there is great scope to develop agents which address this clinically relevant problem.
This dissertation focused on two main strands of research. The first addressed the need for new inhibitors of bacterial efflux pumps. A structure-activity based approach to drug design was utilised, centering on the lead NorA inhibitor 2-phenyl-5-nitro-1H-indole. These synthetic efforts led to the discovery of 2-phenyl-1H-indole-5-carbonitrile (70) as a potential new inhibitor of the NorA pump, with an MIC of 3.6 mM (in the presence of the antibacterial berberine at 100 mg/mL; 269.0 mM) against the NorA wild-type strain of S. aureus. A serendipitous discovery of a novel antibacterial agent, the alcohol (2-phenyl-1H-indol-5-yl)-methanol (75), was made during these studies. This alcohol was found to have a direct antibacterial MIC of 13.4 mM against a NorA pump knockout strain of S. aureus and 28.0 mM against the NorA wild-type and overexpressing strains of S. aureus. This new compound offers a simple, heterocyclic lead compound for future development as an antibacterial agent.
The inter-related second strand of research took advantage of dual action-based approaches to drug design. Several dual action drugs were synthesised which combined an efflux pump-sensitive antibiotic (ciprofloxacin) and efflux pump inhibitor analogue. Of these compounds, 90, 91 and 96 showed promising antibacterial activities with MIC’s of 0.6, 3.9 and 1.5 mM respectively against all three strains of S. aureus (NorA knockout, NorA wild-type and NorA overexpressing). This data confirmed that these dual action drugs were evading this particular resistance mechanism and helped to validate this principle of dual action drug design.
A novel dual action prodrug was also designed and a protected version synthesised. This prodrug contained the antibiotic (ciprofloxacin) linked to an efflux pump inhibitor analogue through a β-lactam nucleus, which was planned to act as a bacterially-specific triggering mechanism. Future work will involve the complete synthesis and testing of this prodrug 122 to assess its antibacterial activity and to determine if it is acting as a dual action prodrug.
02Whole.pdf (3755 kB)