The Nathan lab is in the Department of Microbiology and Immunology at Weill Cornell Medicine in NYC. The lab studies host-pathogen interactions, focusing on macrophages and Mycobacterium tuberculosis (Mtb). Our projects today pursue the following topics: host pathways controlling susceptibility and resistance to Mtb; the genes on which Mtb depends to survive the stresses associated with aerosol transmission; the biology of Mtb in non-replicating (NR) states, during which the pathogen displays phenotypic resistance to conventionally developed antibiotics; and efforts to overcome Mtb’s phenotypic resistance by developing new antimicrobial agents.
We are currently targeting two “hub” enzymes in Mtb—enzymes that participate in multiple functionally distinct complexes, such as lipoamide dehydrogenase, or control the activation of multiple functionally distinct pathways, such as phosphopanthetheinyl transferase. Discovery of the mycobacterial proteasome and its contribution to Mtb’s resistance to host derived reactive nitrogen species has led to the development by Gang Lin and colleagues of proteasome inhibitors not just for Mtb but also for Plasmodium falciparum that spare human constitutive and immunoproteasomes. Gang’s team has also developed non-cytotoxic inhibitors of the human immunoproteasome that spare the constitutive proteasome. With Franck Barrat at HSS and others, we are studying their promise for autoimmune and inflammatory disorders.
These campaigns call on disciplines ranging from immunology and microbiology to biochemistry and medicinal chemistry. Reflecting that, the lab is multi-disciplinary and highly collaborative. Those features apply to the entire Global Health Floor in the Belfer Building, which our lab shares with the labs of Sabine Ehrt, Dirk Schnappinger, Dan Fitzgerald, Kyu Rhee, Kohta Saito and Kate Dupnik. We collaborate as well with Jean-Laurent Casanova and Jeremy Rock at Rockefeller and with Michael Glickman at MSKCC. Still other collaborations with academic partners, pharmaceutical companies and the Global Alliance for TB Drug Development are supported by the Bill & Melinda Gates Foundation’s TB Drug Accelerator. After leading the NIH-funded Tri-Institutional TB Research Unit for the last 7 years, we’re delighted that Sabine Ehrt is PI of the new Tri-I TBRU grant, as we turn our focus to TB transmission in an NIH-funded program project grant (K. Rhee, PI; C. Nathan, co-PI).
