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.