Parasite/Antibiotic Drug Discovery

      IMPDH as a target for antibiotic chemotherapy

 
 

Hedstrom, Lizbeth; Liechti, George; Goldberg, Joanna B. and Gollapalli, Deviprasad R.  The antibiotic potential of prokaryotic IMP dehydrogenase inhibitors.  Current Medicinal Chemistry 18, 1909-18 (2011). [abstract]

Gollapalli, Deviprasad R.; MacPherson, Iain S.; Liechti, George; Goldberg, Joanna B. and Hedstrom, Lizbeth. Structural Determinants of Inhibitor Selectivity in Prokaryotic IMP Dehydrogenases, Chemistry and Biology 17, 1084-1091 (2010). [abstract]  featured in SciBX 3(44); doi:10.1038/scibx.2010.1327.

 

Featured Publications

Microbial infections are now the second leading cause of death worldwide.  Many commonly used antibiotics have been rendered ineffective by the upsurge of drug resistance, and years of neglect have left a mere trickle of new antibiotics in the pipeline.  New targets, and new drugs, are urgently needed.  Although IMPDH inhibitors are used in immunosuppressive, cancer and antiviral therapy, as yet IMPDH inhibitors have not been exploited in antimicrobial applications because no bacterial-selective IMPDH inhibitors have been identified.  We have been engaged in a medicinal chemistry program to develop IMPDH-targeted drugs for treat the biowarfare agent Cryptosporidium parvum.  We have 'in hand' low nanomolar inhibitors of C. parvum IMPDH with

>250 selectivity versus the human enzyme.  Surprisingly, C. parvum IMPDH is most closely related to bacterial IMPDHs.  We have identified the structural motif that defines susceptible enzymes; this motif is found in IMPDHs from a wide variety of pathogenic bacteria, including major treatment challenges such as Mycobacterium tuberculosis, Staphylococcus aureus and Acinetobacter baumannii and potential biowarfare agents such as Bacillus anthracis, Francisella tularensis, Listeria monocytogenes and Burkholderia mallei/pseudomallei.  Several of our compounds display antibacterial activity against M. tuberculosis and F. tularensis.  We are currently investigating the antibiotic potential of IMPDH inhibitors.  The research team includes Greg Cuny (LDDN, Harvard U.), Joanna Goldberg (UVa), Wei Yang (FSU), Barbara Mann (UVa) and Ian Glomski (UVa).  This work is funded by NIH/NIAID R01AI093459.

see also “IMPDH-targeted drugs for cryptosporodiosis” and “Targeting prokaryotic enzymes in a eukaryotic parasite