World TB Day is held on 24 March every year, to mark the day in 1882 when Robert Koch, one of the fathers of microbiology, first announced that he had discovered the cause of tuberculosis (TB) – the bacterium now known as Mycobacterium tuberculosis (link to the TB proteome page in PPS section 5). Over 125 years since its discovery, and despite billions of dollars of investment in drug discovery, this bacterium is still a killer. The World Health Organisation estimates that about two billion people are infected with latent tuberculosis; in 2010, the last year for which full figures are available, over eight million people became ill with active tuberculosis, and 1.4 million people died from the disease. Two factors help make TB particularly deadly: it often occurs in people infected with the HIV virus, where it is one of the major causes of death, and drug resistant forms are becoming more common. In January 2012, Nature reported the identification in India of so-called “totally drug resistant” (TDR) tuberculosis, resistant to all anti-TB drugs in general use.
Image of Mycobacterium tuberculosis bacteria
Photo credit: Janice Carr, Centers for Disease Control and Prevention, USA
In 2012 at Birkbeck, World TB Day coincided with the start of the College’s annual Science Week. Dr Sanjib Bhakta, head of the Mycobacteria Research Laboratory in the Department of Biological Sciences, organised a well-attended symposium on tuberculosis and its treatment. Besides two scientific presentations, the symposium featured a short video, Tuberculosis: The Real Story, highlighting the views of people affected by TB in the UK, and a panel discussion led by the grassroots volunteer organisation Results UK on some of the political challenges raised by tuberculosis.
Both science lectures focused on plants as a source of potential new drugs for tuberculosis. Professor Franz Bucar from the University of Graz in Austria highlighted the extreme chemical diversity of compounds that could be extracted from plants, particularly as compared to those found in the average synthetic compound library. Plants have always existed alongside their own microbial pathogens and have evolved natural antibiotics to protect themselves. Our ancestors, before the dawn of scientific medicine, used plant extracts to treat infectious disease, often quite successfully. The sub-discipline of ethnomedicine involves “mining” these traditional or historical remedies for pure chemicals that can be developed as, or modified into, drugs.
Bucar described a European herb, elecampane or Inula helenium, which is known to have been used to treat lung disease in the sixteenth century. He explained how a complex mixture of natural products derived from this plant had been tested against mycobacteria. Compounds found to have anti-mycobacterial activity were extracted and purified. Other plants have also yielded useful lead compounds; extracts of bark from a small tree with the Latin name of Berchemia discolor have even been shown to inhibit multi-drug resistant strains of Mycobacterium tuberculosis at useful concentrations.
Discovering antibacterial products in plant extracts, however, is only a first step towards drug discovery. Even when natural products like these compounds are found to be selective for bacterial over human cells, it is necessary to discover their mechanism of action; to modify them to optimize their activity; and, since plant sources are often scarce and extraction processes costly, to determine methods of synthesizing them in the laboratory.
The second scientific presentation was given by Dr. Bhakta himself and described current work in Birkbeck’s Mycobacteria Research Laboratory in searching for potential drugs for TB. These are needed not only to combat resistant forms of the bacteria but to improve current treatment regimens for “standard”, drug-sensitive TB. This requires a combination of four drugs to be taken for two months followed by two drugs for another four months, and many patients, particularly poorer and less well educated ones, fail to complete such a long and complex regimen. This in turn can lead to the development of further resistant strains.
Ideally, new drugs are required that target proteins not targeted by existing drugs, as resistance will be harder to develop. Mycobacteria have extremely complex cell walls, unlike those of other types of bacteria; they are essential for the bacteria to survive, and the enzymes used to synthesise them have no equivalents in mammalian genomes. These enzymes, therefore, have many of the characteristics of excellent drug targets. Bhakta and his group have been exploring ways to inhibit the synthesis of the peptidoglycan that is one of the most important constituents of that cell wall. This molecule has been described as the bacterium’s “Achilles heel”, but no drugs targeting its synthesis have yet entered the clinic.
Mycobacteria synthesise peptidoglycan via a series of enzymes known as ligases, each of which adds a new link to the growing peptidoglycan chain. Bhaka’s group has focused on one of these ligases, termed MurE. This enzyme is essential for the bacterium to survive and it is conserved in all Mycobacterium tuberculosis strains. Working in collaboration with Professor Nick Keep, also in the Department of Biology, Bhakta solved the structure of MurE (PDB 2XTA) and showed it to have an active site that could in theory, at least, be occupied, and blocked, by a relatively small, “drug-like” molecule. He and his co-workers are now searching libraries of natural products for compounds that might inhibit this enzyme. They have identified promising MurE inhibitors from plants endemic to both Colombia and China, and are synthesizing analogues of these compounds for further testing.
It is unlikely that the next generation of anti-tuberculosis drugs will include any unchanged natural products. It is extremely likely, however, that natural products will yield the “scaffolds” on which these desperately needed drugs may be built, and perhaps one of these will be generated from within Bucar’s or Bhakta’s groups.