Combination of Subtherapeutic Doses of Tretazicar and Liposomal Amphotericin B Suppresses and Cures Leishmania major-Induced Cutaneous Lesions in Murine Models

Abstract

Cutaneous leishmaniasis (CL) is the most common form of leishmaniasis affecting human populations, yet CL remains largely ignored in drug discovery programs. CL causes disfiguring skin lesions and often relapses after "clinical cure" using existing therapeutics. To expand the pool of anti-CL lead candidates, we implemented an integrated screening platform comprising three progressive Leishmania parasite life cycle forms. We identified tretazicar (CB1954, 5-(aziridin-1-yl)-2,4-dinitrobenzamide) as a potent inhibitor of Leishmania parasite viability across multiple Leishmania species, which translated into complete and prolonged in vivo suppression of CL lesion formation in BALB/c mice when used as a monotherapy and which was superior to liposomal amphotericin B. In addition, oral twice a day administration of tretazicar healed the majority of existing Leishmania major (L.major) cutaneous lesions. In drug combination studies, there was a strong potentiation when subtherapeutic doses of liposomal amphotericin B and tretazicar were simultaneously administered. This drug combination decreased L.major lesion size in mice earlier than individual monotherapy drug treatments and maintained all animals lesion free for up to 64 days after treatment cessation. In contrast, administration of subtherapeutic doses of tretazicar or amphotericin B as monotherapies resulted in no or partial lesion cures, respectively. We propose that tretazicar should be explored as a component of a systemic CL combination therapy and potentially for other diseases where amphotericin B is a first line therapy.