Combination of Subtherapeutic Doses of Tretazicar
and Liposomal Amphotericin B Suppresses and Cures Leishmania
major-Induced Cutaneous Lesions in Murine Models
posted on 2021-02-02, 22:04authored byDiana Caridha, Richard J. Sciotti, Jason Sousa, Brian Vesely, Tesfaye Teshome, Gustave Bonkoungou, Chau Vuong, Susan Leed, Mozna Khraiwesh, Erica Penn, Mara Kreishman-Deitrick, Patricia Lee, Brandon Pybus, John S. Lazo, Elizabeth R. Sharlow
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.