TB: When the drugs don’t work
Kathryn Lougheed on why tuberculosis is still a problem and the key role of basic research in tackling it.
When I tell people that I’m a scientist working on tuberculosis (TB), a large number of the responses tend to be along the lines of, “Oh, is TB still a problem?” Maybe I am taking it too personally, but it sometimes feels as if there is an undercurrent of ‘surely you guys should have, like, cured it already?’
They may have a point though, and it can be a little humbling to realise that while I’ve been in the lab patiently trying to tease apart miniscule aspects of Mycobacterium tuberculosis’s lifecycle, the disease has been rampaging through the developing world, killing more than a million people every year.
TB is a disease of poverty. South-East Asia, sub-Saharan African, India, Russia and certain parts of Latin America carry the majority of the burden. While there are antibiotics that can be used to fight TB, they are not ideal thanks to some nasty side effects and a very long period of treatment. Curing an infection takes around 9 months, and that’s if you have the basic, no-frills-attached version of TB. Drug resistance makes the situation trickier—it can take 28 months to treat these resistant infections and rates of failure are worryingly high.
Part of M. tuberculosis’s huge success as a pathogen is down to its ability to survive in a non-growing form in the human lung—it effectively enters into a state of hibernation. Here, it can remain just below the radar for sometimes decades, only to reactivate and cause disease when the immune system is weakened and can no longer control the bacteria. For this reason, HIV goes hand in hand with TB, dramatically increasing the probability that a latent TB infection will reawaken. The majority of TB drugs unfortunately only work on an active infection—killing something that isn’t growing, that isn’t really doing very much at all, is not an easy task.
So we need new TB drugs, not only to improve on the existing ones but to also replace those being rendered useless by the worldwide problem of drug resistance. Yet for every drug discovery project that yields a new drug, hundreds of others are quietly abandoned when they fall short. The cost incurred by a pharmaceutical company to bring a new drug to market has been touted as being in excess of $1 billion thanks to all the expensive failures littering the path to success.
My last postdoctoral position was in the area of TB drug discovery. The project was to develop inhibitors that could specifically interfere with the function of an essential protein M. tuberculosis cannot live without. This process of finding new drugs is known as target-based drug discovery. Simply put, instead of the old-fashioned method of throwing things at the bacteria and seeing if it dies, target-based drug discovery involves choosing the protein target first and screening thousands, sometimes millions, of small molecules to find one that can inhibit this target in the test tube.
What you’re looking for is a chemical structure that can slot into the protein target and stop it from carrying out whatever vital function it performs. This method is part educated guessing, part trial and error, and once you have a promising inhibitor, you still need to test whether it can kill whole cells. The vast majority don’t tend to do very well at this killing part, in my experience.
This high failure rate has been one of the big issues in antibacterial drug discovery, affecting everyone from small laboratories right up to the big pharmaceutical companies. GSK put a huge amount of effort into target-based drug discovery for several years, looking into something like 300 potential targets, and screening between a quarter and a half a million compounds against 67 of the most promising targets. And they found how many new antibacterials? Um, well it was less than one.
Part of the reason for this expensive lesson in futility was that the compounds they were screening were likely not diverse enough—the libraries were limited to those small molecules that had already been synthesised by chemists. But a key issue that I also encountered in my own more modest attempt at drug discovery is that the protein target being essential to the bacterium isn’t enough. Even if you can inhibit 99 per cent of the target’s activity, the drug isn’t going to work if the remaining 1 per cent is sufficient for survival. What we need is a protein target so important the bacteria cannot tolerate even a small loss of its activity.
Picking good targets for drugs requires us to know more about how the bacterium survives during an infection, so that’s what I am working on now. We’re interested in how the TB bacillus stabilises its important cellular machinery and protects itself during its long periods of hibernation. TB might be very hard to kill when it’s not growing, but this could also be its weakness – if it’s surviving right on the cusp of life and death, then disrupting critical pathways could tip it over the edge.
And TB drug discovery is not all doom and gloom – two new tuberculosis drugs have recently made it to the final stages of clinical trials and are showing great promise in targeting both latent and actively growing bacilli. So yes, TB is still a major problem, but there is still hope it won’t be one day.
Dr Kathryn Lougheed is a research associate at Imperial College London. She works on a Wellcome Trust-funded research studying latent tuberculosis.