Barrels, magnets, and flying insects

Bunch of new reviews by Brandeis authors in press, check one out if you need to catch up on the state of the art.

  • Lisman J, Yasuda R, Raghavachari S. Mechanisms of CaMKII action in long-term potentiation. Nat Rev Neurosci. 2012.
  • Griffith LC. Identifying behavioral circuits in Drosophila melanogaster: moving targets in a flying insect. Curr Opin Neurobiol. 2012.
  • Hedstrom L. The dynamic determinants of reaction specificity in the IMPDH/GMPR family of (beta/alpha)(8) barrel enzymes. Crit Rev Biochem Mol Biol. 2012.
  • Pan Y, Du X, Zhao F, Xu B. Magnetic nanoparticles for the manipulation of proteins and cells. Chem Soc Rev. 2012.

Novel IMPDH inhibitors are candidates for antibacterial drugs

The rise of multiply drug resistant bacteria creates an urgent need for new antibiotics and novel antibiotic targets.  IMPDH, a key enzyme in the biosynthesis of RNA/DNA precursors, is a target for cancer therapy that has not been exploited in antibiotic development. In their recent paper in Chemistry & Biology entitled Structural determinants of inhibitor selectivity in prokaryotic IMP dehydrogenases, Prof. Lizbeth Hedstrom and Brandeis postdocs Deviprasad Golapalli, Iain MacPherson and Suresh Gorla show that selective inhibitors of IMPDH from the protozoan parasite Cryptosporidium parvum also exhibit antibacterial activity. This work could lead to novel treatments for a wide variety of bacterial infections, including some of the most devastating and troubling human pathogens: Mycobacterium tuberculosis, drug-resistant Staphylococcus aureus (e.g. MRSA and VRSA), drug resistant Streptococcus pneumoniae and select agents such as Bacillus anthracis, Burkholderia mallei/pseudomallei and Francisella tularensis.  Importantly, these compounds will spare some commensal bacteria, which should decrease side effects and slow the rise of resistance.  This work suggests that IMPDH-targeted inhibitors can be developed into a new class of broader spectrum antibiotics.

Prodrug activation by Cryptosporidium thymidine kinase

Xin Sun, a Biochemistry grad student from the Hedstrom Lab, discusses her recent paper in J. Biol. Chem.:

I get to say the word “diarrhea” within the first 1-2 sentences of
talking to a stranger about what I work on, and the look I get back is always amusing. We work on developing inhibitors against a human pathogen called Cryptosporidium parvum, a nasty little parasite that causes the aforementioned diarrhea. We specifically zoomed in on the parasite’s nucleotide synthesis pathways to look for potential drug targets. Our recent paper looked at the enyzme thymidine kinase from the parasite, and studied its role in activating a prodrug that we showed to be effective in reducing parasite load in both a cell culture assay,  and in a mouse model.

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