Auranofin Is an Apoptosis-Simulating Agent with <i>in Vitro</i> and <i>in Vivo</i> Anti-leishmanial Activity

Cutaneous leishmaniasis remains ignored in therapeutic drug discovery programs worldwide. This is mainly because cutaneous leishmaniasis is frequently a disease of impoverished populations in countries where funds are limited for research and patient care. However, the health burden of individuals in endemic areas mandates readily available, effective, and safe treatments. Of the existing cutaneous leishmaniasis therapeutics, many are growth inhibitory to <i>Leishmania</i> parasites, potentially creating dormant parasite reservoirs that can be activated when host immunity is compromised, enabling the reemergence of cutaneous leishmaniasis lesions or worse spread of <i>Leishmania</i> parasites to other body sites. To accelerate the identification and development of novel cutaneous leishmaniasis therapeutics, we designed an integrated <i>in vitro</i> and <i>in vivo</i> screening platform that incorporated multiple <i>Leishmania</i> life cycles and species and probed a focused library of pharmaceutically active compounds. The objective of this phenotypic drug discovery platform was the identification and prioritization of <i>bona fide</i> cytotoxic chemotypes toward <i>Leishmania</i> parasites. We identified the Food and Drug Administration-approved drug auranofin, a known inhibitor of <i>Leishmania</i> promastigote growth, as a potent cytotoxic anti-leishmanial agent and inducer of apoptotic-like death in promastigotes. Significantly, the anti-leishmanial activity of auranofin transferred to cell-based amastigote assays as well as <i>in vivo</i> murine models. With appropriate future investigation, these data may provide the foundation for potential exploitation of gold­(I)-based complexes as chemical tools or the basis of therapeutics for leishmaniasis. Thus, auranofin may represent a prototype drug that can be used to identify signaling pathways within the parasite and host cell critical for parasite growth and survival