Mowbray lab

We study how proteins look at the atomic level, and try to understand how that allows them to carry out their many different functions in biology. The overall goal is to apply this information to do useful and interesting things. For example, in many projects we look for small molecules that bind to and block the activity of enzymes important for particular pathogens, and which might be developed into drugs to kill those pathogens. In other projects, we are looking at the details of how enzymes bind to their substrates, and carry out the chemistry they do, in hopes of applying that information to make new and better enzymes. There are so many possibilities!

Popular science presentation

Disease-causing microorganisms place a huge burden on the people of the world. One example is Plasmodium falciparum, the parasite that causes malaria. The World Health Organization (WHO) estimates that a million people, mostly small children in Africa, die of malaria each year, and that half of the world’s population lives in areas where the risk of contracting the disease is high. Another striking example is Mycobacterium tuberculosis, which is thought to infect one-third of world’s population, albeit in an inactive form. When activated, these bacteria cause tuberculosis, which kills approximately 1.4 million people every year. These two diseases are important causes of poverty and suffering in the third world, and the increasing resistance of the relevant pathogens to the available drugs worsens the situation considerably. New drugs are urgently needed, yet there is little incentive for pharmaceutical companies to invest in developing drugs from which they can expect little or no profit. It is therefore important for academic laboratories to take on some of the burden; projects carried out in collaboration with industrial partners seem to offer the best way forward.

More interesting for big pharma, and a more tangible threat for those living in industrialized countries, are the so-called ESKAPE pathogens. These antibiotic-resistant bacteria cause the majority of infections acquired by patients in conjunction with hospital care. Such infections are particularly sinister, since admission to a hospital is intended to cure the patient, not give them an even worse illness than they had upon arrival!

In our lab, we focus on enzymes (catalytic proteins) that pathogens require, but which are not found in humans. We clone, express and purify sufficient quantities of the chosen proteins, and study how they look using a method called X-ray crystallography. In parallel, we try to identify small molecules (inhibitors) that block the function of the pathogen’s enzymes, without harmful effects on the human host. We also design completely new inhibitor molecules, using our knowledge about how the enzymes look, and seek others using high-throughput screening.

Research projects

STOPping pathogens in their tracks

We study enzymes from various pathogens, most often Mycobacterium tuberculosis (tuberculosis), Plasmodium falciparum (malaria) and ESKAPE bacteria (causing antibiotic resistant hospital-acquired infections), using a STOP approach (Same-Target-Other-Pathogen). By studying the structure of particular enzymes, and how small molecules bind to them and thereby affect their function, we are able to identify compounds that are leads in the antimicrobial drug-discovery process.

Some of the enzymes belong to the MEP pathway for isoprenoid biosynthesis (e.g. IspC, IspD and IspE). The terpenoid (isoprenoid) precursors isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) are universally essential because they are required for the production of a vast number of vital biological compounds, including ones needed for steroid biosynthesis, N-glycosylation and numerous other key cellular functions. For many years, the mevalonate or HMG-CoA reductase pathway was believed to be the only way of providing these precursors, which is indeed the case in most eukaryotes, archaea, a few eubacteria, fungi and protozoa such as Trypanosoma, Leishmania and Giardia; statins, for instance, target this pathway. It is now known that most bacteria (including important pathogens such as M. tuberculosis and almost all ESKAPE bacteria), and apicomplexan protozoa (such as malaria parasites), produce their terpenoids via an alternate route called the methylerythritol phosphate (MEP) or non-mevalonate pathway. Inhibition of enzymes of this pathway thus offer good opportunities to injure the pathogens, while leaving the host unharmed.

Additional work focuses on the type II NADH-dehydrogenase (NDH-2) from NAD metabolism. Again, this type of enzyme is essential to many bacteria, but absent from the human host, and is a good target for selectively killing the pathogen.

A typical project involves cloning, expression, purification, assay, crystallization and X-ray structure determination of the relevant protein, with and without bound substrates or inhibitors. And of course, figuring out what it all means, so that we can work with chemists to design and synthesize new molecules with even better properties.

Group members

Research leader: Sherry Mowbray

People

Sherry Mowbray, Professor
sherry.mowbray@icm.uu.se

Lu Lu, PhD student
lu.lu@icm.uu.se, +46-18-471 4018

Adrian Suarez Covarrubias, post-doctoral fellow
Adrian.Suarez@icm.uu.se

Sanjeewani Sooriyaarachchi, post-doctoral fellow
sanjee.soori@icm.uu.se, +46-18-471 4018

Annette Roos SciLife
annette.roos@icm.uu.se, +46-18-471 4984

 

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