World TB Day: Exploring new ways to fight a deadly menace

This post was contributed by Arundhati Maitra, an associate research fellow, Department of Biological Sciences

World TB Day on 24 March marks the day in 1882 when Robert Koch discovered Mycobacterium tuberculosis, the causative agent of one of the most dreadful infectious diseases known to man – tuberculosis (TB). This year, on 21 March, Dr Sanjib Bhakta (Academic Head and Director of the Mycobacteria Research Laboratory, Institute of Structural and Molecular Biology, Birkbeck) chaired a conference organised by EuroSciCon which raised the question – Mycobacterium tuberculosis…Can we beat it?’ The event at The Royal College of Pathologists brought together several great minds in the field of TB research in the UK and from around the world.

The conference began with an introduction to the raging issues in TB management. Dr Bhakta emphasised the fact that an integrative approach is essential to target the various physiological states the germ can exist in inside an infected patient: active state, causing full blown infection, and the latent state, also called persisters, lying dormant within the patient.  

In 1993, WHO reported TB as a global health emergency. The disease continues to remain a serious threat to mankind 20 years on.  Though the TB incidence rates remain constant in the Eurozone, rates in the cosmopolitan cities in the UK such as London, Manchester, etc. speak of a different story. In 2011 the number of TB cases reported in London was higher than that of reported AIDS cases.

In a hard-hitting presentation, Professor Graham Bothamley of Homerton University Hospital, UK, remarked that the failure to contain the disease is largely due to the lack of political commitment and roadblocks in health care delivery. A survey across Europe showed that not only are drugs unavailable in some regions, but the regimens followed in various countries do not follow the tested, WHO approved guidelines, putting many lives at risk.

The essential requirements to lessen the burden of TB are twofold – speedy and accurate diagnostics and development of novel drugs and treatment regimens.  

Diagnosis by sputum microscopy and culture tests are the predominant methods of TB detection. Professor Mike Barer from the University of Leicester reported an interesting finding which could have far reaching effects in latent TB detection. His group has recently discovered that sputum analysis, usually used to detect active infection could also give an insight to the level of persister population in the patient by detecting presence of lipid bodies in the bacteria.

Though remarkable, this still doesn’t answer the need for a rapid and accurate means of TB detection. That is what Christopher Granger, Director of Oxford Immunotech Ltd claimed to have achieved. He described the T Spot TB test, a simple test based on ELISpot assay, which is more specific than the regular tuberculin skin test, detects latent infection and is time as well as cost-effective. However, Dr Jayne Sutherland from the MRC Unit in Gambia mentions that a simple dip-stick test that can be available at the point-of-care is essential in the areas with highest incidences of TB. She described how many of the clinics are in remote areas and can only be referred to as ‘bush clinics’, lacking necessary infrastructure for TB detection. Her team is engaged in developing lateral flow based tests, something similar to the pregnancy test kits available today.

New diagnostic equipment to detect TB is being developed at the University of Amsterdam by Ngoc Dang. It detects biomarkers of lipid origins by thermally assisted hydrolysis and methylation followed by gas chromatography and mass spectroscopy. This equipment, when available, would have positive implications in areas where a large number of samples need to be tested.

Moving on to drug development and treatment strategies, Professor Stephen Gillespie of the University of St Andrews discussed several new anti-tubercular drugs and shorter treatment regimens in various phases of clinical trials. He also emphasised the need to develop predictive models for regimens as newer drugs are being discovered.

Detection of targets specific to the infectious agent is essential for the development of novel drugs. A couple of these targets were discussed by Dr Luke Alderwick from Birmingham University and Professor Edith Sim from Kingston University. While Dr Alderwick focussed on a cell wall synthesising enzyme, DprE1 and its inhibitor benzothiazinone (BTZ), Dr Sim focussed on enzymes essential for the bacteria’s survival within host cells, N-acteyl transferase and HsaD. Dr Brian Henderson from UCL described the role of proteins that have more than one specific function (moonlighting proteins) in virulence of these bacteria and suggested that these could be potential targets.

A common theme was observed in presentations by Dr Anthony R.M. and Professor Tim Mc Hugh. Both were strong proponents for the need to monitor the progress of treatment in the earlier stages rather than the current practice of 18 months on. The former explained a ‘treat to test’ strategy following the belief that upon starting of treatment an initial burst of dead cells makes for easy detection of the kinetics of the response of the host to treatment. The latter suggested the use of various biomarkers obtained from the bacteria and the host such as colony counts to assess bacterial load, bacterial RNA and small RNA from the host, to indicate the effectiveness of the treatment and likelihood of a relapse.

An interesting Q&A session began with a question regarding the importance of point-of-care diagnostics and was led by Dr Bhakta to touch on the other issues plaguing TB management today. Dr Juan D Guzman from ISMB, Birkbeck was asked to comment on the scaffolds found in natural and synthetic compounds that are especially effective as anti-tubercular drugs.

Poster presentations were invited and the top prizes went to Ngoc Dang, University of Amsterdam for her work on TB diagnostics and Dr Tulika Munshi from ISMB, Birkbeck, for her poster on ATP-dependant Mur ligases as novel therapeutic targets for TB drug development (http://dx.plos.org/10.1371/journal.pone.0060143).

On the whole, the conference was one step towards defeating TB as interdisciplinary research, collaborations and alliances are urgently required to fight this menace.

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Birkbeck Commemorates World TB Day by Discussing Drugs from Plants

This post was contributed by Clare Sansom, a part-time lecturer in Birkbeck’s Department of Biological Sciences, and a freelance consultant and science journalist.

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. 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.

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 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.

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