Researchers from three South African universities are unleashing the power of oxygen in a triple-drug treatment strategy against disease-causing parasites and bacteria.
Oxygen is the key to life – and that applies as much to parasites and bacteria that cause malaria, tuberculosis (TB) and certain other related diseases as it does to humans and animals.
However, unlike the high-performance athlete who really would like to have more oxygen to break that elusive world record, these parasites and bacteria – known collectively as pathogens – cannot have too much oxygen, for it becomes dangerous to them.
They just need sufficient oxygen to carry on their nefarious disease-causing activities, in particular in reproducing.
These pathogens usually infect those parts of the human body which tend to carry a lot of oxygen – for example the blood for the malaria parasite, or the lungs for TB. They have cunningly evolved elaborate biological defence systems that stop them being harmed by too much oxygen.
Medicinal chemists around the world know this but have struggled for years to try to develop safe and effective drugs that somehow can overcome the defence systems so that eventually the excess oxygen can kill the pathogen, without of course harming the patient.
However, in addition to using the drugs that destroy the pathogen's defence systems against oxygen, it is important to have another type of drug that has a different way of killing the pathogen.
Three drugs tackle the problem of resistance
“Remember that disease-causing bacteria and parasites are notoriously capable of becoming resistant to drugs,” says Prof Richard Haynes of the North-West University’s (NWU’s) Centre of Excellence in Pharmaceutical Sciences (Pharmacen) and leader of the "MALTB Redox" Flagship Project of the South African Medical Research Council.
“This means they can rapidly overcome effects of drugs that in the beginning would have killed them by interfering with one or more vital biological processes that maintain the life of the pathogen.
“We all have heard of development of bacteria resistant to most known antibiotics and how serious a problem this is worldwide. What we need in addition to our new drugs that overcome the defences of the pathogens against excess oxygen, is to have yet another drug with a different killing mechanism,” he says.
“So overall, we require a drug cocktail comprising three drugs. Ideally we need two drugs to help each other break down the pathogen's defence systems against oxygen, and the third drug that interferes with a completely different life-maintaining biological process in the pathogen. In this way, it becomes very difficult for the pathogen to develop resistance.”
Coming up with three drugs is no easy task. However, researchers from the NWU, the University of Pretoria (UP) and the University of Cape Town (UCT) believe they are on the way to developing new drug combinations that have the potential to be effective against malaria, TB and other related diseases.
"This is exciting. If all goes well, and all indications suggest this, we will have new a combination of drugs that will be effective against malaria and eventually, by applying the same principles, against TB," says Prof Haynes.
Why this approach stands out
Of course, drug combinations – especially against malaria and TB – are nothing new. However, these researchers’ scientific approach towards choosing the drugs that make up the combination, is new.
“It is remarkable that, for example, drug combinations currently used for treatment of malaria have largely been chosen because the individual drugs are already out there, and generally not because of any consideration or understanding of how the drugs actually kill the malaria parasite,” Prof Haynes says.
“In our case, we choose the initial two-drug combination because when the drugs destroy the defence of the parasite against oxygen, they become oxidatively stressed. If the environment is sufficiently oxygen rich, they die.”
The third drug type works in a completely different way – which is exactly what is required for the new triple combinations – by inhibiting the ability of the pathogen to grow and replicate itself. The drug derivatives produced in the NWU/UCT/UP project have been found to be active against both the malaria parasite and the TB bacterium.
New drugs for TB a very real prospect
"For TB, we are now ready to carry the work forward by conducting more advanced TB testing in animal models, and then hopefully later we will be able to move to clinical trials on humans," says Prof Haynes.
“The work being done through this collaboration presents the very real prospect of new drugs for TB. The expectation is that such drugs will not have the shortcomings associated with other TB drugs, notably problems with toxicity and with drug-resistant strains of TB.”
In reaching this point, he says the support of the SA Medical Research Council has been invaluable. The exceptional collaboration between the NWU, UP researchers led by Prof Lyn-Marie Birkholtz for malaria, and the UCT researchers, led by Prof Digby Warner for TB and by Prof Lubbe Wiesner for evaluation of drug properties, also plays a big role.
The only obstacle standing in the group’s way is funding. If that is forthcoming from the donor community, then the project can proceed quickly.
“We really do need urgent solutions to the enormous problems currently associated with treating some of the diseases that cause untold suffering among millions of people.”
The ins and outs of the triple-drug actionHere is an overview of the drug types in the triple-drug treatment strategy of the NWU/UCT/UP researchers. The first two drug types directly break down the pathogen's defence systems against oxygen. The third drug type works completely differently. Drug type one The Haynes' group conducted chemical studies on artemisinin and by modifying certain parts of the molecule came up with a newer derivative they called artemisone, which does not have the drawbacks of artemisinin when being used as a drug for treatment of malaria. Artemisinin and its chemical derivatives, including artemisone, help to break down the defence of the malaria parasite against oxygen. Drug type two The two drugs help each other in being even more effective in not only killing the blood stages of the malaria parasite, but also in killing those stages of the malaria parasite involving the mosquito. In other words, the drug combination helps to prevent the parasite from being taken up by the mosquito and therefore infecting another person with malaria when the mosquito that normally carries the parasites flies off to bite another person. Methylene blue is also known to break down the defences of the malaria parasite to oxygen, and this is why it was originally chosen in the combination with the artemisinin drug. However, methylene blue tends to cause patients to have blue perspiration and blue urine. Thus, new drugs work in the same way but do not have these strange side effects are being examined. Drug type three The problem with decoquinate is that it is an intractable substance reminiscent of powdered bricks. It does not dissolve in water or oil, so has to be given as a solid. This is not suitable for treating human patients, especially if they are very sick with malaria or TB. The NWU team solved the problem by using chemical transformations to make new chemical derivatives of decoquinate that are much more soluble. What is important here is that the chemical reactions used are not complicated and are easily carried out, which is important as drugs for malaria or TB must be economical. Several of the derivatives were found by the UP collaborators to be highly active against the malaria parasite. Other derivatives were found by collaborators at the UCT Molecular Mycobacteriology Research Unit headed by Prof Digby Warner to be active against the TB bacterium. In addition, collaborators at UCT headed by Prof Lubbe Wiesner of the Division of Clinical Pharmacology with the PhD students Lloyd Tanner and Lizahn Laing, have shown that the derivatives have properties suitable for carrying forward for eventual evaluation in clinical trials. |
Prof Richard Haynes of the NWU’s Centre of Excellence in Pharmaceutical Sciences (Pharmacen).
