Molecular mechanisms of cell death and nephrotoxicity

Pathophysiology and Therapy of Immune and Inflammatory Diseases
Hospital Universitario Fundación Jiménez Díaz

   Infections caused by multidrug resistant (MDR) Gram-negative bacteria have become a serious problem worldwide and can result in sepsis with high mortality. Though the need for new drugs that target MDR-Gram negative bacteria is widely acknowledged, no new treatment options have emerged. It has been predicted that if antibiotics become ineffective, routine surgeries will end in mortalities for 1 in 6 patients.

   Colistin (also known as polymyxin E) is one of the few remaining therapeutic options available to treat life-threatening infections caused by MDR Gram-negative bacteria. Clinically, colistin is administered parenterally as sodium colistin methanesulphonate (CMS), an inactive pro-drug that is converted into colistin, the antibacterial and toxic entity. The early use of CMS/colistin was linked to high rates of toxicity, especially nephrotoxicity, and therefore its use waned until its recent resurgence due to increasing resistance in Gram-negative bacteria.

    In this project we want characterize the molecular mechanism of colistin-induced nephrotoxicity. The final goal is to find new treatments that protect the kidneys, avoiding the colistin-induced renal injury for the patients with MDR Gram-negative infections and, thus, allowing the use of higher dose that improves the antibacterial activity.

   To carry out the project we will use cultured renal cells and experimental animal models and will take advantage of the large expertise of the lab in the field, including the use of novel nephroprotective compounds for which we hold patents or are applying for them. In summary the project will involve the following methods: cell viability assays, confocal microscopy, and flow cytometry to test and characterize cell death, western blot or ELISA and RT-PCR to study protein and mRNA expression respectively, treatment with specific inhibitors of cell death to characterize molecular pathway of death in cell and animal models, use of systems biology databaaes.

Biomolecules & Cell D.
Molecular Biomedicine
Ana Belen Sanz Bartolome