A Structural Approach for Treating Drug Resistant Fungal Pathogens

Summary

Principal Investigator: Mitchell W Mutz
Abstract: DESCRIPTION (provided by applicant): There is an urgent need to discover more effective therapeutic regimens for fungal infections. Nosocomial infections caused by Candida albicans have a 50% mortality rate. Aspergillosis is a leading cause of death in organ transplant recipients, as well as patients suffering from cancer and auto-immune disorders. The annual cost of treating fungal infections is about $2.6 billion in the United States and is increasing due to the larger number of immunocompromised patients who suffer from these illnesses. The emergence of fungal drug resistance to widely used antifungals including triazoles and echinocandins further compromises the efficacy of the limited armamentarium of antifungal therapeutics. A number of in vitro and in vivo studies have established that molecules which inhibit the fungal protein, calcineurin, are highly synergistic with several important classes of antifungal therapeutics including triazoles and echinocandins. However, a great challenge with exploiting fungal calcineurin as a therapeutic target is the structural similarity to human calcineurin, and that inhibition of human calcineurin causes severe immunosuppression and toxicity. By solving the X-ray crystal structure of calcineurin from C. albicans, we hope to gain insight into the structure activity relationships of non- immunosuppressive cyclosporin A analogues. We hope to develop these cyclosporin A analogues as potent antifungals employing the following steps: 1. Homology model the known x-ray crystal structure of the ternary complex of H. sapiens calcineurin/cyclosporin A/cyclophilin A to create a model of the ternary structure of C. albicans calcineurin/cyclopsorin A/cyclophilin A. 2. Determine the x-ray crystal structure of the ternary complex of C. albicans calcineurin, cyclosporin A, cyclophilin A. 3. Design and synthesize cyclosporin A analogues by comparing the human ternary structure with the fungal ternary structures generated by the homology model and/or x-ray model and employing molecular modeling tools to assist with library design. 4. Screen and select compounds against both C. albicans and non-albicans Candida strains.
Funding Period: 2012-07-01 - 2014-06-30
more information: NIH RePORT

Detail Information

Research Grants30

  1. Acute Humoral Rejection of Renal Allografts
    Robert L Fairchild; Fiscal Year: 2013
    ..This project will utilize a novel mouse model to investigate graft-reactive antibody induced mechanisms that mediate the acute or chronic kidney graft injury that causes the loss of kidney transplants ..
  2. Transcontinental EM Initiative for Membrane Protein Structure
    David L Stokes; Fiscal Year: 2013
    ..abstract_text> ..
  3. Resolution Mechanisms in Acute Inflammation: Resolution Pharmacology
    CHARLES NICHOLAS SERHAN; Fiscal Year: 2013
    ..Selected synthetic SPM will be scaled-up for demonstration of their unique mode of action in vivo in a resolution pharmacology core using experimental disease models. Our broad goal is to bring forth new treatments in resolution. ..
  4. Pacific NorthWest Regional Center of Excellence (PNWRCE)
    Jay A Nelson; Fiscal Year: 2013
    ..pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease. ..
  5. Pacific Southwest RCE for Biodefense &Emerging Infectious Diseases Research
    Alan G Barbour; Fiscal Year: 2013
    ..abstract_text> ..
  6. Mechanisms Underlying Chronic Lung Pathology
    Wayne Mitzner; Fiscal Year: 2013
    ..This tightly integrated, synergistic program will thereby provide new insights into the mechanisms that underlie the pathogenic progression of chronic lung diseases. ..
  7. Antifungal drug target prioritization using Cryptococcus neoformans
    Alexander Idnurm; Fiscal Year: 2013
    ..The discovery of these essential genes represents new avenues for the development of antifungal agents. ..
  8. Oxidation in Inflammation and Cardiovascular Disease
    Stanley L Hazen; Fiscal Year: 2013
    ..It may also lead to important insights for atherosclerosis risk assessment, diagnosis and therapy. ..
  9. EINSTEIN AGING STUDY
    Richard B Lipton; Fiscal Year: 2013
    ..Together, these Projects will help disentangle the multifactorial processes that lead to cognitive and locomotor decline and dementia. ..
  10. Dissecting triazole resistance and transcriptional regulation of ergosterol homeo
    Haoping Liu; Fiscal Year: 2013
    ..albicans. Identification of smal molecules and their targets will lead to the discovery of novel pathways and mechanisms that control ergosterol homeostasis and triazole resistance. ..
  11. Genetic and Evolutionary Basis of Fungal Drug Resistance
    Zhenglong Gu; Fiscal Year: 2013
    ..This work may improve diagnosis and treatment strategies for pathogenic fungal infection. ..
  12. Genome Integrity in Candida albicans
    Judith G Berman; Fiscal Year: 2013
    ....
  13. Small molecule protein-glycan inhib. as malaria transmission-blocking therapuetic
    RHOEL DAVID RAMOS DINGLASAN; Fiscal Year: 2013
    ....