Group leader
Tuberculosis
(TB) is a bacterial infection that is re-emerging as a world health emergency, due
in part to its co-occurrence with HIV infection, and the development of treatment-resistant
strains of the bacterium. It is estimated that one third of the world’s population
is infected with the latent form of TB; of these, each year 9 million people will
develop the active, contagious form of the disease, and of these 2-3 million will
die from their infection. The current treatment for TB requires that a cocktail
of antibiotic drugs be taken continuously for at least six months. There is an urgent
need for more active, shorter regimen treatments for TB, particularly against the
dormant and drug-resistant forms.
The New York-based
Global Alliance for TB Drug Development (GATB) is currently sponsoring a
clinical trial of the first radically different anti-TB drug to be developed in
40 years, known as PA-824. PA-824 is particularly active against the dormant stages
of TB and it began phase 2 trials in human volunteers in 2008.
Global Alliance for TB Drug Development |
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Current research
- Our group was awarded funding from the GATB to develop second-generation analogues
of PA-824, seeking to establish more potent activity and an improved pharmacokinetic
profile. The Auckland chemistry team, based at the Auckland Cancer Society Research
Centre, comprises five medicinal chemists who have to date prepared nearly 1000
compounds for evaluation against cultures of the TB bacterium. Many highly active
compounds have now been identified, the most promising of which have been prepared
in sufficient quantities to enable their evaluation in mouse models of TB. The selection
of a number of compounds which have significantly better activity than PA-824 for
advanced in vivo evaluations is almost complete, after which the chemistry efforts
on the project will focus on providing larger quantities of the drugs required for
these studies. The biological evaluation of these compounds is being carried out
by Professor Scott Franzblau and his team at the
Institute for Tuberculosis Research, University of Illinois at Chicago.
- The activity of PA-824 and its analogues is believed to result from their metabolic
activation within the bacterium. In a collaboration with
Associate Professor Bob Anderson's group in the Chemistry
Department, investigations of the novel reductive chemistry of PA-824 and its analogues
are underway, to better understand the mode of action of this new class of prodrugs.
- A major problem arising from the chemotherapy of most infectious diseases is the
development of resistance to the treatment drugs. This is certainly the case for
TB, where the appearance of multidrug resistant (MDR) and more recently, extensively
drug resistant (XDR) forms of TB is now well documented. The development of drug
resistance can typically be reduced by the administration of a cocktail of antibacterial
drugs which have different mechanisms of action. An alternative and relatively novel
approach to overcoming the development of drug resistance is to design multifunctional
drugs, which combine the key features of several active agents within the one drug
molecule. Such compounds would ideally attack several drug targets in the bacterium
simultaneously. These molecules could ultimately prove to be more active than the
component drugs alone, and have the potential to simplify and shorten drug therapy.
The GATB has recently awarded new funding to the Auckland group to develop such
hybrid molecules for the treatment of TB. The biological evaluation of these multifunctional
molecules is being carried out by
Assistant Professor Anne Lenaerts’ team at Colorado
State University.
Recent publications
- Thompson, A.M., Blaser, A., Anderson, R.F., Shinde, S.S., Franzblau, S.G., Ma, Z.,
Denny, W.A., Palmer, B.D. Synthesis, reduction potentials and anti-tubercular activity
of ring A/B analogues of the bioreductive drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine
(PA-824). J. Med. Chem., 2009, 52, 637-645.
- Anderson, R.F., Shinde, S.S., Maroz, A., Boyd, M., Palmer, B.D., Denny, W.A. Intermediates
in the reduction of the antituberculosis drug PA-824, (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine,
in aqueous solution. Org. Biomol. Chem., 2008, 6, 1973-1980.
Group members
