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.