Cyclopalladated Compound 7a Induces Apoptosis- and Autophagy-Like Mechanisms in Paracoccidioides and Is a Candidate for Paracoccidioidomycosis Treatment

• Published in: Antimicrobial agents and chemotherapy Vol. 59; no. 12; pp. 7214 - 7223
• Main Authors: Arruda, Denise C, Matsuo, Alisson L, Silva, Luiz S, Real, Fernando, Leitão, Jr, Natanael P, Pires, Jhon H S, Caires, Antonio Carlos F, Garcia, Daniel M, Cunha, Fernanda F M, Puccia, Rosana, Longo, Larissa V G
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01-12-2015
• Subjects: Animals; Antifungal Agents; Antifungal Agents - chemical synthesis; Antifungal Agents - pharmacology; Apoptosis - drug effects; Autophagy - drug effects; Cadaverine - analogs & derivatives; Cadaverine - biosynthesis; Candida albicans; Candida albicans - drug effects; Candida albicans - growth & development; Caspases - genetics; Caspases - metabolism; Chromatin - drug effects; Chromatin - pathology; Chromatin - ultrastructure; Cryptococcus neoformans; Cryptococcus neoformans - drug effects; Cryptococcus neoformans - growth & development; DNA Fragmentation - drug effects; Dose-Response Relationship, Drug; Experimental Therapeutics; Fungal Proteins - genetics; Fungal Proteins - metabolism; Gene Expression; Life Sciences; Lung - drug effects; Lung - microbiology; Lung - pathology; Male; Mice; Mice, Inbred BALB C; Organometallic Compounds; Organometallic Compounds - chemical synthesis; Organometallic Compounds - pharmacology; Palladium; Palladium - chemistry; Palladium - pharmacology; Paracoccidioides; Paracoccidioides - drug effects; Paracoccidioides - genetics; Paracoccidioides - growth & development; Paracoccidioides - ultrastructure; Paracoccidioidomycosis; Paracoccidioidomycosis - drug therapy; Paracoccidioidomycosis - microbiology; Paracoccidioidomycosis - pathology; Superoxides - metabolism; Vacuoles - drug effects; Vacuoles - pathology; Vacuoles - ultrastructure
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.00512-15

Paracoccidioidomycosis (PCM), caused by Paracoccidioides species, is the main cause of death due to systemic mycoses in Brazil and other Latin American countries. Therapeutic options for PCM and other systemic mycoses are limited and time-consuming, and there are high rates of noncompliance, relapses, toxic side effects, and sequelae. Previous work has shown that the cyclopalladated 7a compound is effective in treating several kinds of cancer and parasitic Chagas disease without significant toxicity in animals. Here we show that cyclopalladated 7a inhibited the in vitro growth of Paracoccidioides lutzii Pb01 and P. brasiliensis isolates Pb18 (highly virulent), Pb2, Pb3, and Pb4 (less virulent) in a dose-response manner. Pb18 was the most resistant. Opportunistic Candida albicans and Cryptococcus neoformans were also sensitive. BALB/c mice showed significantly lighter lung fungal burdens when treated twice a day for 20 days with a low cyclopalladated 7a dose of 30 μg/ml/day for 30 days after intratracheal infection with Pb18. Electron microscopy images suggested that apoptosis- and autophagy-like mechanisms are involved in the fungal killing mechanism of cyclopalladated 7a. Pb18 yeast cells incubated with the 7a compound showed remarkable chromatin condensation, DNA degradation, superoxide anion production, and increased metacaspase activity suggestive of apoptosis. Autophagy-related killing mechanisms were suggested by increased autophagic vacuole numbers and acidification, as indicated by an increase in LysoTracker and monodansylcadaverine (MDC) staining in cyclopalladated 7a-treated Pb18 yeast cells. Considering that cyclopalladated 7a is highly tolerated in vivo and affects yeast fungal growth through general apoptosis- and autophagy-like mechanisms, it is a novel promising drug for the treatment of PCM and other mycoses.