‘Curdlan’ explored to treat TB and other ills

CURDLAN is a popular carbohydrate in the food industry. Its name is derived from the word “curdle” and, as it suggests, it’s widely used as a thickener and stabiliser in everything from sausages to milk substitutes.

More recently, it has caught the eye of the pharmaceutical industry. That’s because curdlan, itself produced by bacteria, is able to trigger an antibacterial response in a range of environments and organisms. Among other uses, researchers are looking at curdlan as a possible treatment for cancers and other diseases.

One of the diseases is TB, the infection responsible for killing more people than any other infectious disease in human history. South Africa has one of the world’s highest TB burdens.

South Africa’s combined burden of TB, TB/HIV and multidrug-resistant TB (MDR-TB), driven by socio-economic factors and its high HIV numbers, is especially worrying.

Remedies made up of cocktails of antibiotics are not effective against MDR-TB. This has sparked interest in finding alternative treatments. It’s why our research group at the School of Pharmacy at UWC, and others, are beginning to test the efficacy of curdlan as a potential drug candidate.

In a recent paper, for instance, we show promising results for the potential treatment of TB using curdlan-based nanoparticles.

Our work centres on developing host-directed therapies using curdlan. Such treatments essentially let the human immune system do the heavy lifting. This is done by activating its natural antibacterial mechanisms while controlling the inflammation that results from such activation. Inflammation is a signal that the immune system is working. But if inflammation is out of control, it can cause major damage to human tissue, as seen in severe Covid-19 infections.

Research has shown that host-directed therapies hold immense potential for the treatment of TB.

To understand how the therapies work, it’s important to understand how TB infection unfolds in the human body. Primary TB infection occurs when a person inhales aerosol droplets, released by contagious individuals, that contain Mycobacterium tuberculosis (M.tb). This is the bacterium that causes TB. Once inhaled, M.tb quickly makes its way to the lung’s alveolar space, made up of tiny air sacs at the end of the bronchioles, the air passages inside the lungs.

Here, it is absorbed by alveolar macrophages, the lung cells that are usually the first line of defence against pollutants and pathogenic organisms. Typically the macrophages would trigger an immune response in the body. But M.tb has evolved so cannily that it eludes or switches off this immune-triggering response in the macrophages. The alveolar macrophages become its infection headquarters; the bacterium remains concealed within the cells.

For any treatment to be successful, it has to navigate a host of obstacles to reach M.tb. It must make its way through complex lung lesions, then penetrate the cell membrane of macrophages and other host cells, and finally be taken up by the M.tb sitting within the cells.

That’s where nanoparticles enter the picture. Traditional drugs are taken orally or intravenously. They travel throughout the body via the blood circulatory system. Many drug molecules do not reach their targets, staying in the body where they cause negative side effects.

That’s where nanoparticle-based treatments have the upper hand: they are extremely small and extremely targeted and their release into the system is controlled. Smaller doses are required and there is less dispersion around the body, meaning fewer side effects. All the factors suggest that nanoparticle-based treatments might be the right approach to take against TB. And two findings from our study bolster the case.

First, we observed the production of what’s known as pro-inflammation cytokines, a signalling molecule that triggers an antibacterial effect in immune cells. This meant that the nanoparticles were doing what they were meant to do.

Second, we found that the M.tb bacteria in the immune cells were considerably reduced over 72 hours.

There is much more work to be done, but it’s an important step towards tackling TB – in South Africa and everywhere else.