Susana Frases Carvajal – Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Brazil
Luis R. Martinez – University of Florida, USA
Níura Madalena Bila – Eduardo Mondlane University, Mozambique
Brazil and Mozambique
Microbial Pathogenesis
Cryptococcus neoformans
Cryptococcal meningoencephalitis (CME) represents a devastating neurological crisis, claiming 112,000 lives annually with 73% of deaths concentrated in sub-Saharan Africa. This fungal brain infection disproportionately affects HIV-positive individuals, accounting for approximately 20% of AIDS-related deaths globally. Current treatment regimens—amphotericin B, 5-fluorocytosine, and fluconazole—present significant challenges including severe toxicity, limited accessibility, and high costs, creating an urgent unmet medical need. Our groundbreaking research has identified four US FDA approved central nervous system (CNS)-penetrant molecules with remarkable anti-cryptococcal activity and favorable toxicity profiles. These compounds—N-oleoyl-dopamine, Q134R, JCN037, and BAY 11-7082—represent potential therapeutic breakthroughs for this neglected disease. Through rigorous evaluation of clinical isolates from Mozambique and Brazil, we will characterize these small molecules’ anti-cryptococcal efficacy, mechanisms of action (MOA), and fungal resistance profiles. The most promising candidate will advance to testing in a mouse model of CD4 T cell deficiency that authentically replicates HIV/AIDS immunosuppression in humans and CME pathology. We will assess the drug candidate efficacy in mouse survivability, fungal clearance, immune response induction, and neurological function maintenance. This innovative therapeutic pipeline addresses a critical global health challenge by potentially delivering safer, more effective treatment options for vulnerable populations. Our research could transform CME management, significantly reducing mortality and improving outcomes for patients worldwide who currently face limited therapeutic options.
