World Tuberculosis Day: past progress and future perspectives
To raise awareness for World Tuberculosis Day (March 24th), I discuss the work my team is doing to develop improved, shorter treatments to tackle this challenging infectious disease.
World TB Day arrives on 24th March every day, which provides us with an opportunity to reflect on our progress in eradicating this disease. As an infectious disease, there are two main approaches we can take, one is to develop vaccines to prevent infection, the other is to develop drugs which can treat the disease. At IDRI (Infectious Disease Research Institute), we work in both these areas, but my work focuses on discovering new drugs for tuberculosis (TB) (1).
Many people think that TB is a disease of the past, but it still kills over 1 million people every year, and over 9 million people develop TB every year. Most people would be used to taking a course of antibiotics for a few days or a week, but TB treatment takes a minimum of six months with multiple drugs. For example, the current therapy recommended by the World Health Organization requires four antibiotics for the first two months, and then two antibiotics for the remaining four months. There is also an increasing problem of drug resistance making our current antibiotics ineffective. For drug resistance, it can take 12-24 months to treat. This makes it obvious that we urgently need new drugs that will work more quickly and more effectively.
Our goal is to discovery new drugs that are effective at curing drug-sensitive and drug-resistant tuberculosis and which shorten the time it takes to cure disease. Our research covers drug target identification and validation, high throughput screening and medicinal chemistry. In addition, we work to understand the pathogenic mechanisms and basic biology of the bacterium that causes TB, (Mycobacterium tuberculosis) and use this information to inform drug discovery. This involves a number of scientific disciplines, so we have both chemists and biologists working closely together every day.
We run phenotypic screens to find hit compounds with activity against the virulent bacteria, and then our chemists work to improve these molecules to make their biological and physicochemical properties appropriate as new treatments. As we are dealing with an intracellular pathogen which can survive and replicate in macrophages, we also look for molecules that can work against both extracellular and intracellular bacteria (in macrophages), as well as molecules with activity against antibiotic-tolerant or non-replicating bacteria. We will also profile other properties, such as the kinetics of bacterial kill, activity under different conditions, the frequency at which resistance arises, and the activity against drug-resistant isolates.
As a microbiologist, there are several challenges in working with M. tuberculosis. As an infectious agent which infects via the respiratory route, we have to work under strictly controlled and safe laboratory conditions. In the USA we work under Biosafety Level 3 conditions which require specialized laboratories and very tightly controlled protocols. In addition, the bacteria grow very slowly (as compared to other organisms) - on average they divide once every day, whereas bacteria like Escherichia coli divide every 20-30 minutes - this means that our experiments take a long time. We often have experiments which take a few months to complete, and our quickest experiments to test compound activity take a week. When you put these two challenges together (and there are others), it is apparent why the pace of drug discovery for TB is inherently slow and can take many years to get from screening to drug candidate.
Having been in the field for more than 20 years, I have seen many changes. Although the drug pipeline for TB still looks pretty sparse, and the area is still underfunded, we do see hope for new drug candidates coming through in the near future and beyond. The most recent changes have seen the establishment of a number of consortia, bringing together groups from academia, non-profits, large pharma companies, and small biotech, all working together towards a common aim. For example IDRI is part of the Lilly TB Drug Discovery Initiative (2) and the TB Drug Accelerator (3), each involving multiple partners, and works closely with industry to identify and develop novel drugs. In our own work, we have seen projects develop from screening large compound sets – we have screened over ½ million compounds so far – into leadgeneration where we are improving both activity and drug-like properties of our hit molecules. We work closely with our collaborators and partners to bring all of our expertise to bear in order to reach our goal in the quickest way. We view this collegial way of workingas more efficient and effective, and we are already seeing the benefits in term of progress in our internal projects and joint publications. We hope that this will enable us to reach our goal of contributing to an improved and shorter TB treatment.
Tanya Parish. Vice President, Drug Discovery. TB Discovery Research, Infectious Disease Research Institute, Seattle.