The nucleotide biosynthetic pathways provide a rich source of drug targets such as dihydrofolate reductase, the target of the widely used antibacterial drug trimethoprim. IMP dehydrogenase (IMPDH) presents a similar therapeutic opportunity. Although IMPDH inhibitors are used in immunosuppressive, cancer and antiviral therapy, as yet IMPDH inhibitors have not been exploited in antibacterial 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 treating the category B parasite Cryptosporidium parvum. We have 'in hand'low nanomolar inhibitors of C. parvum IMPDH (CpIMPDH) with >250 selectivity versus the human enzymes. Surprisingly, CpIMPDH is most closely related to bacterial IMPDHs, suggesting that C. parvum obtained this gene via horizontal transfer. We have identified a structural motif that defines susceptible enzymes;this motif is found in a wide variety of pathogenic bacteria, including seven other select agents. We propose a program to develop the CpIMPDH inhibitors as broader spectrum antibiotics. To this end, we will determine the efficacy of the CpIMPDH inhibitors against a panel of pathogenic bacteria chosen to define the spectrum of action in terms of the structural variation of the target enzyme and the permeability of the bacteria (select agents in bold): Bacillus anthracis (Gram positive), Francisella tularensis (Gram-negative facultative intracellular), Listeria monocytogenes (Gram- positive facultative intracellular), Burkholderia mallei/pseudomallei (Gram-negative facultative intracellular), Staphylococcus aureus (Gram-positive) and Acinetobacter baumannii (Gram-negative). These pathogens pose some of the most serious threats to human health;B. anthracis, Bu. mallei/pseudomallei, and F. tularensis are top priorities for countermeasure development and methicillin-resistant S. aureus (MRSA) and A. baumannii present major treatment challenges.

Public Health Relevance

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. This proposal outlines a project to develop novel antibacterial drugs with activity against a wide variety of Gram-positive and Gram-negative bacteria. Potentially susceptible organisms include eight biowarfare agents, MRSA, and other extensively resistant strains.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI093459-02
Application #
8249803
Study Section
Special Emphasis Panel (ZAI1-LG-M (J1))
Program Officer
Franceschi, Francois J
Project Start
2011-06-01
Project End
2016-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
2
Fiscal Year
2012
Total Cost
$1,058,736
Indirect Cost
$211,339
Name
Brandeis University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
616845814
City
Waltham
State
MA
Country
United States
Zip Code
02454
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Makowska-Grzyska, Magdalena; Kim, Youngchang; Gorla, Suresh Kumar et al. (2015) Mycobacterium tuberculosis IMPDH in Complexes with Substrates, Products and Antitubercular Compounds. PLoS One 10:e0138976
Kim, Youngchang; Makowska-Grzyska, Magdalena; Gorla, Suresh Kumar et al. (2015) Structure of Cryptosporidium IMP dehydrogenase bound to an inhibitor with in vivo antiparasitic activity. Acta Crystallogr F Struct Biol Commun 71:531-8
Makowska-Grzyska, Magdalena; Kim, Youngchang; Maltseva, Natalia et al. (2015) A novel cofactor-binding mode in bacterial IMP dehydrogenases explains inhibitor selectivity. J Biol Chem 290:5893-911
Sun, Zhuming; Khan, Jihan; Makowska-Grzyska, Magdalena et al. (2014) Synthesis, in vitro evaluation and cocrystal structure of 4-oxo-[1]benzopyrano[4,3-c]pyrazole Cryptosporidium parvum inosine 5'-monophosphate dehydrogenase (CpIMPDH) inhibitors. J Med Chem 57:10544-50
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