World TB Day: A Q&A with Professor Tanya Parish

Posted on March 22, 2019   by Microbiology Society

Sunday 24 March marks World Tuberculosis Day. On this day in 1882, Robert Koch announced he had discovered the causative agent of tuberculosis (TB), which was a major development in understanding the disease and working towards finding treatment options. In this post, we discuss TB research with Professor Tanya Parrish, Editor-in-Chief of the Society's flagship journal, Microbiology, and Head of the TB Discovery Research Group at the Infectious Disease Research Institute (IDRI) in the US.

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You are currently Head of the TB Discovery Research Group at IDRI. When did you start there and what does your role entail?

I have been at the Infectious Disease Research Institute (IDRI) for 11 years. My role is to lead the drug discovery efforts within IDRI. Our major focus is on developing new drugs for tuberculosis, but we also work on other pathogens including non-tuberculous mycobacteria and Leishmania. My role is similar to that of a Professor/Principal Investgator in an academic environment, in that I provide scientific direction, mentorship and bring in external funding to support our work. I am also an Affiliate Professor at the University of Washington where I participate in the pathobiology graduate program and carry out a small amount of teaching.

Why is Mycobacterium tuberculosis such a challenging pathogen to work with?

M. tuberculosis is challenging for a number of reasons. Firstly, it is a slow-growing organism, it only divides every 24 hours in culture, which means experiments take a very long time. We need three to four weeks to get colonies on an agar plate and most of our experiments last for several months.

Secondly, mycobacteria have very lipid-rich, waxy cell walls - this means that they stick together (clump) in culture and are challenging to lyse if we want to run studies on intracellular components such as nucleic acids and proteins. Finally, and most importantly, M. tuberculosis is a respiratory pathogen, so we work in a highly controlled, specialized laboratory setting (Biosafety Level 3 in the US, Containment Level 3 in the UK). 

What are the main research questions you and your team are trying to answer?

We have two main areas of our work. The first is focused on identifying and developing new drugs for tuberculosis. This involves the entire team and utilizes microbiology expertise, as well as high throughput screening, chemistry, biochemistry and pharmacology.

The second area is investigating how new drugs work to kill the bacteria, so we focus on the mode of action of new molecules, the understanding of essential cellular processes, and mechanisms of antibiotic resistance in mycobacteria. We also have a strong interest in novel drug targets involved in cell wall biosynthesis and the electron transport chain.

What research techniques does this involve?

We use a huge range of techniques. For our basic research we use a large range of microbiological growth assays and macrophage-infection studies to monitor bacterial survival. We also use whole genome sequencing, transcriptomics, proteomics and metabolomics to look at bacterial responses to new drugs. For target identification, we use molecular techniques and gene manipulation to study the role of individual genes. For our drug discovery work, again we use the full range of microbiological techniques, but we also use robotics and microplate readers for liquid handling and screening. In addition, we have a synthetic chemistry group who make our new molecules and we analyse these with mass spectrometry and nuclear magnetic resonance.

How do you manage the risks of working with this pathogen in the lab? Do you have to take extra precautions?

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We have a specialized laboratory which is engineered to provide protection. The laboratory is subject to strict regulation and control; for example, it is maintained under negative pressure at all times. We have a long training process and standard operating procedures which detail how we can carry out our experiments. We also have extra personal protection equipment (PPE) including Tyvek suits, booties, hairnets and respiratory protection (either face masks or full “powered, air-purifying respirators”).

When did you start researching this pathogen and what makes it so fascinating to you?

I started my work on mycobacteria right back during my PhD studies, where I was looking at gene regulation in the non-pathogenic species Mycobacterium smegmatis. After that, I moved onto studies on the basic biology and physiology of M. tuberculosis for my post-doctoral work and I have been working on it ever since. M. tuberculosis is a complex organism which can survive in different states and can persist in the environment and in the human lung for long periods of time. I have always been interested in gene regulation and how bacteria respond to the environment. Pathogenesis and virulence come from specific responses to the infection environment, so it was a natural progression to look at those processes. In addition, the cell wall is particularly interesting, since it is the only part of the bacterium that directly contacts and interacts with the environment. In M. tuberculosis the cell wall plays a major role in immune evasion and bacterial survival. So this host-pathogen interplay is fascinating.

What have been some of your greatest research achievements so far?

I have been working in this field for over 25 years, so singling out particular studies is difficult. However, one of the areas I think that has been the most rewarding and most likely to deliver something meaningful, has been the opportunity to bring my microbiological expertise into a drug discovery setting. Having a multidisciplinary team working in close concert is incredibly rewarding and is the only way that we will be able to reach our goals. Our recent work on developing and implementing a number of phenotypic screens has lead to us identifying a number of promising lead molecules.

Antimicrobial resistance in TB has been identified by the World Health Organization as a public health crisis. How does the pathogen develop resistance and how are new treatment options being developed? 

TB is the biggest problem in antimicrobial resistance, and there are around 0.5 million cases of multi-drug resistant (MDR) TB each year. Resistance in M. tuberculosis is exclusively from chromosomal mutations in contrast to other bacteria, where it is often plasmid-mediated. For the frontline drugs, resistance is usually independently to each antibiotic. For some of the antibiotics, there are multiple different mutations that can lead to resistance. The majority of resistance is generally acquired after treatment – the treatment for TB is lengthy with multiple drugs – and poor patient compliance and/or access to drugs often leads to resistance developing during therapy. However, transmission of resistant strains is becoming an increasing problem. The aim in developing new drugs is to find novel drug targets, so that pre-existing clinical resistance is not a problem and that we can have a “universal regimen” for all TB patients.

What do you think the future of TB research looks like? Where do you think the field will be ten years from now?

TB research has expanded over the last 20 years and now addresses not just the basic biology, physiology and pathogenesis, but also vaccine, drug and therapeutic development. I think that there will be an expansion of research into understanding the nature of latency or dormant bacilli and increased efforts to determine how antibiotics kill the organism. I also anticipate that there will a better understanding of the host-pathogen interaction and how antibiotics interact with the immune response. Ten years from now, I hope that the outcome of all this effort will be at least one totally new drug regimen for TB, as well as a new and effective vaccine. Alongside this, we should have a much better understanding of the mechanisms by which M. tuberculosis adapts its physiology to drug treatment.

To read some of the newest findings in TB research, read the Mycobacterium tuberculosis Collection, which contains recently-published papers on M. tuberculosis.
Tanya has also written a Microbe Profile Mycrobacterium tuberculosis: humanity's deadly microbial foe in Microbiology. To find out about how TB has shaped the history of the UK, read our blog Has TB had its time?