Design of inhibitory drugs for molecular components of the siderophore biosynthetic pathway that are crucial for iron sequestration during mycobacterium tuberculosis (TB) pathogenesis
Associate Professor Tony Velkov
+ 61 3 834 49846
Tuberculosis (TB) remains a major health problem in the world and new anti-tuberculosis drugs are urgently needed to shorten the time for chemotherapy, to combat the spread of drug-resistant TB, and to treat the latent form of TB infection. The rapidly emerging resistance of TB to many front-line antimicrobials highlights the importance of the development of effective antitubercular agents against new targets which cannot easily attain mutational resistance.
In this regard, mycobactin siderophores represent novel and ideal targets due to their essential role in the vital processes of iron acquisition and transport during infection by TB. Genetic disruption studies have demonstrated the mycobactin biosynthetic pathway to be essential for host infection. Because iron plays a key role in the development of the infectious disease state of TB, the mycobactin biosynthetic enzymes represent outstanding and novel candidates as targets for developing antibacterial agents against TB.
This project represents a novel and innovative approach to develop drugs against drug resistant TB based upon:
- Targeting the ability of TB to attain virulence as opposed to conventional antibiotic drug treatments that target the viability of TB and its ability to replicate.
- The essential role of the mycobactin biosynthetic machinery in the virulence of TB, and the fact we are targeting each enzyme in the pathway means it is very unlikely to evolve resistance to inhibitory drugs over time.
- Targeting all of the enzymes in the biosynthetic pathway to further safeguard against resistance.
- The highly conserved nature and complexity of this pathway means drugs that come into development are likely to be effective against all drug resistant TB strains.
The implementation of drugs that emerge from this work will lead to safer and shorter dosing regimes by inhibiting the virulence of TB. This allows the host's natural immune system to rapidly eliminate the infection. More importantly, this will limit the spread and emergence of resistant TB. These drugs will be of considerable benefit in immunocompromised individuals such as AIDS patients, who often suffer prolonged TB infections. Moreover, given that these enzymes are unique to bacteria, drug therapies should have little or no toxic effects on the host.
The principle aim(s) of this project include:
- Clone and purify recombinant forms of each enzyme in the mycobactin biosynthetic pathway.
- Obtain high resolution crystallographic structures of each enzyme using synchrotron radiation.
- In silico screening, together with conventional high-throughput robotic screening of each enzyme target with fragment and several compound libraries.
- Obtain high resolution crystallographic structures of each enzyme-drug complex using synchrotron radiation.
- Test each lead compound for the ability to inhibit mycobactin biosynthesis in laboratory cultures of TB and in the test tube with the reconstituted biosynthetic pathway.
This research project is available to Honours, Master of Biomedical Science to join as part of their thesis.
Please contact the Research Group Leader to discuss your options.
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