Hunt to eradicate drug-resistant diseases

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The search for new or better combinations of drugs is under way in earnest and the NWU's Centre of Excellence for Pharmaceutical Sciences in the Faculty of Health Sciences on the Potchefstroom Campus is at the heart of it. "We have already had some encouraging findings. In particular, we are confident of being able to develop a drug that is effective against resistant malaria," says Prof Richard Haynes, leader of the MALTB REDOX Flagship research programme.

With funding for three years from the Medical Research Council, the programme is spearheading the development of oxidant and redox drug combinations for treating malaria, TB and others such as toxoplasmosis, an opportunistic parasitic disease. Prof Haynes is leading a multinational team of medicinal chemists, malaria and TB biologists and others from universities in South Africa, Australia, Argentina, Germany, Hong Kong and the US, most of whom are researching a different aspect of drug development.

"Many medicinal chemistry groups and drug screening groups are involved with the various activities associated with this programme. This multipronged approach reflects the urgency of the search for effective ways to counter the onslaught of malaria and TB in particular."

Most vulnerable region

Sub-Saharan Africa is a region that is potentially the most vulnerable to an outbreak of drug-resistant malaria. Malaria is a huge problem in this region, killing an estimated 500,000 people a year, the majority of them children. Deaths could increase significantly if the drug-resistant malaria now appearing in Southeast Asia spreads to Africa.

It is important to note that the emergence of drug-resistant malaria has been a problem in the past, such as in the late 1950s and early 1960s. However, renewed hope in controlling malaria was provided after a remarkable drug called Artemisinin and its derivatives were first discovered and developed in China in the late 1970s and early 1980s. "These drugs are famous for their rapidity in killing the malaria parasite in the body. However, they are chemically quite fragile and break down easily in the body. Therefore, for optimum effect they had to be combined with other antimalarial drugs that are chemically robust and last for a much longer time in the body.

"In this way the use of these so-called Artemisinin combination therapies or ACTs turned out to be very effective in curing malaria." Indeed, there was a 25% decrease in mortality worldwide from 2000 to 2011, and a 33% decrease in mortality in Africa, according to the World Health Organisation. For 2012 and 2013, there were 207 million cases and 62,000 deaths, mostly among African children.

Drug resistance: the reason for urgency

"So the prognosis looked good, could we extrapolate into the future and look forward to eliminating malaria...? Clearly not, for something dreadful happened quite recently. In Southeast Asia, the malaria parasite has become resistant to the Artemisinin combination therapies (ACTs)."

While various arguments have been put forward for this resistance, it is clear that part of the problem vests in the continued use of the 'original' Artemisinin in the ACTs and a lack of rational consideration in the use of the partner drug in the combination. "Be that as it may, these ACTs are essentially the only effective drugs we have left. If the resistant parasite spreads to Africa, it will be a catastrophe. Therefore, the need to develop rational new drug combinations to stop the spread of the resistant malaria parasite is a task of the utmost urgency. As part of this strategy we must use a new Artemisinin derivative."

When it comes to drug-resistant TB, the situation in Sub-Saharan Africa is equally dire. "Notably there has been a 45% decrease in mortality in most countries since 1990, but unfortunately not in South Africa where there has been an increase according to the World Health Organisation statistics."

It is also common knowledge that Multidrug Resistant (MDR) TB is on the increase. This means that the TB bacterium has become resistant to treatment with at least two of the most effective anti-TB drugs, isoniazid and rifampicin. Now a potentially more serious problem has emerged, that of 'extensively drug-resistant (XDR) TB'. This means that the TB bacterium is resistant to most frontline drugs used to treat TB and MDR-TB.

Pathogens pose similar challenges

How is it that we can develop drugs to treat resistant malaria, TB and toxoplasmosis? "It is remarkable that when one studies the biology of the malaria parasite especially when it is in the blood of humans, the TB bacterium especially when it lodges in cells in the lungs. The toxoplasmosis parasite when it is also in the human, similarities emerge in the way we think we can kill these pathogenic organisms."

These pathogens develop a means of protecting themselves from the assault of highly reactive breakdown products of atmospheric oxygen, and from biological iron, both of which they require for their own metabolism. These species are called 'reactive oxygen species' or ROS. Additionally for the TB bacterium, it has to contend with related species called 'reactive nitrogen species' uniquely present in its special environment in the body.

"Thus the strategy that we need to use is to overcome the defences of these pathogens against these reactive species. They pose similar challenges in terms of drug development: we need drugs that directly damage the relevant cellular machinery in the pathogen that keep the generation of these reactive species under control.

"Once the control is lost, then the pathogen, malaria parasite, TB bacterium or toxoplasmosis parasite, is killed by the reactive species. This is why the MALTB REDOX tea is looking at these different disease pathogens together."

Leaving no pathway unguarded

However, it is critical to bear in mind that using a single drug to attack and kill a pathogen may result in resistance that is, the parasite or bacterium can cleverly alter its cellular machinery to counter the effect of that drug. "Therefore, we need to use another drug that has a subtly different way of killing the pathogen. Its mode of action will be slightly different to the first drug. It then becomes more difficult for the pathogen to alter its machinery to counter the effects of two different drugs. To be absolutely certain, we will also use a third drug that kills the pathogen by a completely different pathway."

The first drug from this project is called an 'oxidant' drug that will be based on a new Artemisinin or related drug. The second, which will help the oxidant drug, is called a 'redox' drug, a classical example of which is methylene blue. The latter helps the first drug by undergoing a process in the cell called redox cycling which is associated with the continued generation of ROS. The third component will be a drug with a completely different mode of action.

Many-layered problem

"However, this is only part of the problem. In terms of the individual pathogens, the task of getting each of the drugs to attack at the right place is a formidable one. For example, the TB bacterium has a waxy coating that can be very difficult for a drug to penetrate. In the case of malaria, it may be difficult to get enough of the drug into the blood stream to be effective against the parasite, or to attack other stages of the parasite that normally occur in the liver." Therefore, the team is also working out the best way to get the drugs inside the parasite or bacterium as the case may be.

"This area of drug development is called 'formulation', and it is critically important. In summary, our research proposal was based on how some of the drugs work and how these may have a common pathway leading to the killing of each pathogen. In principle, we should be able to use the same type of drug for TB, malaria and toxoplasmosis. The caveat is that we must also use an additional but different drug in combination with the first drugs to suppress the emergence of resistance in each case. It is a complex, many-layered problem that the team is tackling systematically, bringing a wealth of global expertise to bear in their search for solutions," concludes Prof Haynes.