Sunday, 1 April 2012

Transition State Analogues - A New Wave of Antibiotics


Bacterial infection. Two words that can alone, put terrible images in your head. Syphilis, gonorrhoea, tuberculosis, salmonella, staph infection; these are some of the horrors that we as a civilisation have spent the last 100 years trying to battle. Since the discovery and use of antibiotics such as penicillin, dating back to the 1940s, many diseases caused by infection of bacteria have become treatable. These antibiotics were responsible for saving thousands of lives in the second world war, and have saved millions of lives ever since. 

The problem we face with antibiotics is that they aren't a complete solution to the problem. Antibiotics place bacteria under pressure to mutate, and so the longer a disease is treated with an antibiotic, the more resistant that bacteria becomes to that antibiotic, meaning that we have to continuously come up with new drugs to maintain the upper hand. One of the bacteria which has become more and more resistant to treatment is the chief bacterium causing malaria, Plasmodium falciparum.  

This bacterium is responsible for the deaths of approximately 1,000,000 people every year, and it has been shown to have developed a resistance to the traditional treatment drugs of chloroquine, quinine and tetracycline. However, Vern Schramm of the Albert Einstein College of Medicine has recently developed a new drug to combat our bug in a different way. Using new molecular modelling techniques, he has developed a way to determine the shape of some enzymes when they are in their transition state; something that only lasts for a femtosecond (1 x 10-15 ), which we are unable to observe in any natural way. 

Identifying the transition state of the enzyme 'P. falciparum purine nucleoside phosphorylase' (PfPNP), within the bacterium, he has developed a drug that mimics one of the natural chemicals in the metabolic pathway and therefore occupies PfPNP, stopping it from performing its normal function. Figure 1 shows the relevant metabolic pathways of the bacterium. It is taken from the research article on which the news article is based. It can be found at this link: http://dx.doi.org/10.1371/journal.pone.0026916

Figure 1: Metabolic Processes of P. falciparum
http://www.plosone.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjournal.pone.0026916.g001&representation=PNG_M
We have two key metabolic pathways to consider (a longer, more detailed explanation of this process and the chemicals involved can be found in the research article), in the first:

  • PfADA processes MTA into MTI
  • PfPNP processes MTI into hypoxanthine
  • Hypoxanthine is required to produce IMP
  • IMP is required to produce purines/nucleic acids.

In the second, MTA is recycled as it is inhibitive to the production of other enzymes in the polyamine synthesis process, shown in the top right of the diagram. What this means is that 
PfPNP is vital to allowing both processes to function. Naturally, if we stop PfPNP from doing its job, the bacterium will die, as we prevent purine salvage and also prevent polyamine synthesis,  stopping cell growth. 


To block PfPNP, the drug “BCX4945” was created. The results of the testing of this new drug, both in vitro and in vivo, are that P, falciparum was killed quickly and effectively. In vivo testing in Aotus monkeys revealed that if the drug was administered for 7 days, the bacterium was cleared, and then after several days without drug presence, the bacterium reappeared with a low growth rate.
 
So far, not enough testing has been done to identify the effectiveness of the drug in regards to bacterium mutation, however similar developments in a drug that stops E. Coli and Vibro cholerae, have revealed no loss in effectiveness after 26 generations of mutations. (Woodbury, 2012)

This research is exciting as the bacterial-clearing properties of the new drugs can be combined with preventative medicines in order to treat malaria effectively in the future, and there is a high likelihood that this new type of drug will spark no resistive mutation, the problem that has prompted this new solution.



Oscar Richardson
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References:

Woodbury, M.A. 2012, Superfast drugs target shape-shifting enzymes, New Scientist. Viewed 18 March 2012.  http://www.newscientist.com/article/dn21579-superfast-drugs-target-shapeshifting-enzymes.html

Cassera MB, Hazleton KZ, Merino EF, Obaldia N III, Ho M-C, et al. (2011) Plasmodium falciparum Parasites Are Killed by a Transition State Analogue of Purine Nucleoside Phosphorylase in a Primate Animal Model. Viewed 18 March 2012 http://dx.doi.org/10.1371/journal.pone.0026916




 

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